Antioxidant Alternatives in the Treatment of Amyotrophic Lateral Sclerosis: A Comprehensive Review

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that produces a selective loss of the motor neurons of the spinal cord, brain stem and motor cortex. Oxidative stress (OS) associated with mitochondrial dysfunction and the deterioration of the electron transport chain has been shown to be a factor that contributes to neurodegeneration and plays a potential role in the pathogenesis of ALS. The regions of the central nervous system affected have high levels of reactive oxygen species (ROS) and reduced antioxidant defenses. Scientific studies propose treatment with antioxidants to combat the characteristic OS and the regeneration of nicotinamide adenine dinucleotide (NAD⁺) levels by the use of precursors. This review examines the possible roles of nicotinamide riboside and pterostilbene as therapeutic strategies in ALS.

Oxidative Stress

Most eukaryotic organisms need oxygen to ensure the normal functioning of cellular energy metabolism, which is an evolutionary advantage and a highly efficient form of energy production (Jie et al., 2013). In the electron transport chain (ETC), oxygen is partially reduced by the incorporation of an electron, generating a free radical as a secondary product (Falkowski and Godfrey, 2008; Venditti et al., 2013). Free radicals are atoms or molecules that have one or more unpaired electrons in their last orbital layer (Chandrasekaran et al., 2017), which makes them strongly reactive capable of carrying out chain reactions, responsible for the oxidative damage of cells and tissues (Solleiro-Villavicencio and Rivas-Arancibia, 2018). They are classified as ROS and reactive nitrogen species (RNS) (De Gara and Foyer, 2017). Also included are reactive iron species (RIS) (Dixon and Stockwell, 2014) and copper species (RCS) (Gyulkhandanyan et al., 2003). The main ROS are: superoxide anion radicals (O), hydroxyl radicals (OH^∙) and hydrogen peroxide (H₂O₂) (Popa-Wagner et al., 2013). The RNS include: nitric oxide radical (NO^∙), nitroxyl anion (NO^–), nitrosonium cation (NO⁺) and peroxynitrite anions (ONOO^–) (Halliwell, 2012; Rogers et al., 2014; Zuo et al., 2015).

The production of ROS is mainly secondary to enzymatic reactions involved in the respiratory chain, activity of cytochrome p-450, synthesis of prostaglandins and phagocytosis (Pizzino et al., 2017). Mitochondrial activity and metabolism of cytochrome p-450 are the most contributing sources in mammalian cells (Jha et al., 2017) (Figure 1).

FIGURE 1

Mitochondrial production of ROS may occur on the external membrane, internal membrane or in the mitochondrial matrix, during physiological and pathological conditions (Pizzino et al., 2017). O production occurs when there is a buildup of nicotinamide adenine dinucleotide phosphate (NADPH) or when there is a reduced CoQ pool within the mitochondria (Murphy, 2009). O may also be secondary to the enzymatic activity of lipoxygenases (LOX) and cyclooxygenases (COX) (Valko et al., 2007) during the arachidonic acid metabolism and by endothelial and inflammatory cells (Al-Gubory et al., 2012). O may participate in reactions that produce H₂O₂ or OH^∙ (Kumar and Pandey, 2015) (Figure 1).

The cytochrome p-450 enzymes present in the liver are an important source of ROS production and their function is to catalyze O producing reactions by NADPH dependent mechanisms (Liochev, 2013). The risk of ROS production here is high because it contains transition ions, oxygen and electron transfer processes (Liochev, 2013). In addition, there are a group of NOX (NADPH oxidases) enzymes located on the cell membrane of polymorphonuclear cells, macrophages and endothelial cells, that facilitate the conversion of oxygen into superoxide on biological membranes using NADPH as an electron donor with ROS released as secondary products (Atashi et al., 2015) (Figure 1). Endothelium xanthine dehydrogenase interacts with xanthine oxidase (XO) producing O and H₂O₂, and thus, generating another source of free radicals (Turrens, 2003) (Figure 1).

Non-enzymatic reactions may also be responsible for the production of ROS by the reaction of oxygen with organic compounds and after cellular exposure to ionizing radiation (Valko et al., 2007) (Figure 1).

The endogenous release of RNS, such as nitric oxide (NO^∙), is produced from L-arginine in reactions of catalyze by three main isoforms of nitric oxide synthase (NOS): epithelial NOS, neuronal NOS and inducible NOS, which are activated in response to various endotoxin or cytokine signals (Förstermann and Sessa, 2012). Thus oxygen can react with this NO^∙ and form highly reactive molecules such as ONOO^– (Salisbury and Bronas, 2015; Sharina and Martin, 2017) (Figure 1).

Endogenous production of reactive oxygen and nitrogen species (RONS) can be conditioned by exogenous pro-oxidant factors: environmental and atmospheric pollution, water pollution, chemicals like pesticides or industrial solvents, heavy metals or transition metals, different types of xenobiotics, irradiation by UV-light, X-rays or gamma rays, stress, tobacco, smoked meat, the use of waste oil and malnutrition (Phaniendra et al., 2015; Niedzielska et al., 2016; Solleiro-Villavicencio and Rivas-Arancibia, 2018; Zewen et al., 2018) (Figure 1).

Reactive oxygen and nitrogen species at physiological concentrations are regulators of numerous cellular functions: cellular signaling pathway, control of cell survival, regulation of vascular tone, signal transduction by cell membrane receptors, membrane renewal, synthesis and release of hormones, increase of inflammatory cytokine transcription regulation of the immune system (Robberecht, 2000; Ray et al., 2012), phosphorylation of proteins, action on ionic channels and transcription factors, production of thyroid hormones and crosslinking on extracellular matrix (Brieger et al., 2012).

The body tries to maintain redox homeostasis between the production of RONS and the capacity for their removal by antioxidant systems (Zuo et al., 2015), which allows the redox state to be re-established after temporary exposure to high concentrations of RONS and minimize the risk of a deteriorated redox homeostasis, which is an unbalanced state known as OS (Sies, 1986; Coyle and Puttfarcken, 1993; Liguori et al., 2018) (Figure 1). However, redox homeostasis is conditioned by the magnitude and duration of exposure to free radicals, since constant exposure can have a serious impact on intracellular signals or genetic expression, resulting in irreversible pathological consequences (Rhee et al., 2003), since most reactions of the body are dependent on the redox state (Tan et al., 2018).

Diseases associated with OS, such as neurodegenerative diseases, are related to aging (Liguori et al., 2018), a physiological stage accompanied by progressive loss of tissue and organ function (Flatt, 2012), changes in regulatory processes, decrease in the antioxidant capacity of the organism and irreversible tissue damage by RONS that compromises the achievement of a redox balance (Romano et al., 2010). The damage caused by oxidation depends on the defects of the enzymes involved in the redox signaling pathways (Tan et al., 2018).

Free radicals can cross the cells and cause modifications in the main macromolecules (lipids, proteins and nucleic acids), damaging their structure and altering their normal function (Salisbury and Bronas, 2015). Lipid peroxidation is associated with different disease states and is responsible for an unstable cell membrane, oxidation of low-density lipoproteins (LDL) and poly-unsaturated fatty acids (PUFAs). The oxidation of different amino acids such as lysine, arginine, proline and threonine results in protein dysfunction. Oxidative damage of DNA generates severe mutations and adverse effects on transcription, producing an RNA more vulnerable to oxidation. Chronic persistence of this situation is capable of causing cell death (Huiyong et al., 2011; Dizdaroglu and Jaruga, 2012).

OS plays an important role in chronic, inflammatory pathologies (Kehrer and Klotz, 2015), progressive brain damage and the pathogenesis of neurodegenerative diseases such as: Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Multiple sclerosis (MS), Huntington’s disease (HD), and Spinocerebellar ataxia (SA) (Dias et al., 2013; Islam, 2017; Zewen et al., 2018) (Figure 1).

Oxidative Stress and Neurodegenerative Diseases

The exact pathogenesis of neurodegenerative diseases remains unknown, although a complex and multifactorial origin has been established in which aspects such as genetic predisposition, certain endogenous factors and exposure to environmental factors are involved (Correia and Moreira, 2010; Correia et al., 2010; Coppedè and Migliore, 2015). ROS is a key factor in the etiology of these pathologies (Bhat et al., 2015) and in patients with a neurodegenerative disease, high levels of OS biomarkers have been observed (St-Pierre et al., 2006; Niedzielska et al., 2016). However, physiological concentrations of free radicals play an important role in normal brain function (De Silva and Miller, 2016; Scialò et al., 2017; Chen et al., 2018). Thus, ROS can contribute to: vascularization, cerebral perfusion, cellular signaling, synaptic plasticity, neurotransmitter secretion and cerebral vasodilation (Massaad and Klann, 2011; Grochowski et al., 2018; Neal and Richardson, 2018). A moderate increase of ROS secondary to mitochondrial activity produces preconditioning that leads to a neuroprotective function against harmful agents and is even preventive against massive ROS formation (Dirnagl and Meisel, 2008; Jou, 2008; Dirnagl et al., 2009). The origin of the problem lies in impaired redox homeostasis, which causes damage to cell membrane, compromising the viability and integrity of the central nervous system (CNS) (Van Horssen et al., 2011; Payne and Chinnery, 2015). The excess of ROS is related to changes in the microcirculation of the brain (Freeman and Keller, 2012; Staiculescu et al., 2014). O and H₂O₂ are able to cause a contraction of cerebral blood vessels (Allen and Bayraktunan, 2009). Increased levels of H₂O₂ are associated with increased pro-apoptotic agents in brain vascular cells (Li et al., 2003) and OS can alter cerebral vascular function through an interruption of NO^∙ signaling and consequently, its vasodilatory and anti-inflammatory capacity (Miller et al., 2010; De Silva and Miller, 2016). In addition, ROS contribute to the maintenance of a proinflammatory state, secondary to secretion of cytokines and chemokines (Hsieh and Yang, 2013; Kehrer and Klotz, 2015).

The CNS is especially susceptible to oxidative damage (Cordeiro, 2014). The brain is largely formed by PUFAs with high sensitivity to lipid peroxidation (Nunomura et al., 2006), motor neurons are highly sensitive to OS (Simpkins and Dykens, 2008) and the CNS has a poor antioxidant capacity with low activity of protective enzymes such as glutathione peroxidase (GPx), catalase (CAT) or superoxide dismutase (SOD) and poor capacity for cell regeneration (Fischer and Maier, 2015; Kim et al., 2015; Formella et al., 2018). Although the brain only accounts for 2% of body weight (Mergenthaler et al., 2013) and mitochondrial density is higher in myocytes than in neuronal cells (Gandhi and Abramov, 2012), it is an organ with a high metabolic rate that can consume up to 20% of the total oxygen of the body (Moreira et al., 2009; Ronnett et al., 2009). This means it has 10 times higher energy and glucose consumption than the other tissues and a high dependence on mitochondrial energy production, responsible for the increase of ROS (Carvalho and Moreira, 2018). Taking into account the high rate of demand and energy consumption of the brain, the majority of mitochondrial mutations can affect the functioning of the CNS and have been associated with neurodegenerative diseases (Angelova and Abramov, 2018). Thus, mitochondrial dysfunction is currently seen as a “convergence point” in neurodegeneration (Correia et al., 2010; Bennett et al., 2014; Arun et al., 2016; Kurtishi et al., 2018).

Mitochondrial dysfunction compromises the energy supply of ATP to neurons, calcium homeostasis and leads to high levels of ROS that accelerate the mutation rate of mitochondrial DNA (mtDNA) and lipoperoxidation of neuronal membranes, causing decomposition of PUFAs and the formation of highly reactive end products: malondialdehyde (MDA) and 4-hydroxy-2-nonenal (HNE) (the most toxic species related to cell damage and apoptosis) (Petrozzi et al., 2007; Albarracín et al., 2012; Fritz and Petersen, 2013) (Figure 1). Accumulation of mutations in mtDNA causes an increase in oxidative damage, a decrease in energy rate and an increase in ROS. Thus, mitochondrial dysfunction generates a “vicious-cycle” responsible for neuronal damage, genetic mutations and metabolic stress, a situation that can lead to apoptosis (Van Houten et al., 2006; Selvaraji et al., 2019; Wang et al., 2019).

Mitochondrial dysfunction is considered as the main cause of neurodegenerative diseases pathogenesis (ALS, PD, AD, MS, HD) (Lin and Beal, 2006; Federico et al., 2012) (Figure 1). Postmortem studies in brains of patients with these diseases have found that mitochondrial dysfunction is a common event leading to the degeneration and death of neuronal cells (Schon and Manfredi, 2003; Bao and Swaab, 2018; Du et al., 2018).

Brain aging increases sensitivity to OS and decreases the effectiveness of antioxidant defenses, causing functional deficiencies, inflammation, decreased elasticity and greater susceptibility to the etiological factors involved in the pathogenesis of neurodegenerative disease (Federico et al., 2012; Guo et al., 2013). It also contributes to the accumulation of mutations in the mtDNA, malfunctions in the oxidative phosphorylation pathway and impaired redox homeostasis (Sarasija and Norman, 2018).

ROS have currently been proposed as one of the main contributors to the development and progression of neurodegenerative diseases (Morató et al., 2014). There is evidence that indicates that the increase in RONS concentration is a inducer of tissue damage, activation of microglia and astrocytes, neuronal dysfunction, neurodegeneration and cell death (Federico et al., 2012; Morató et al., 2014; Schieber and Chandel, 2014). Thus, a “vicious cycle” between OS, mitochondrial dysfunction, aging and neuroinflammation has been demonstrated (Witte et al., 2010; Van Giau et al., 2018). However, further studies are necessary to understand the physiopathological mechanisms implicated (Schetters et al., 2018) because it is unknown whether OS is a primary cause that induces the initiation of neurodegenerative diseases or if it is a side effect associated with the spread of damage to nerve cells (Jenner, 2003; Emerit et al., 2004).

Amyotrophic Lateral Sclerosis

ALS, also known as Charcot’s disease or Lou Gehrig’s disease, was originally described by Jean-Martin Charcot and Joffrey (Chen et al., 2013; Niedzielska et al., 2016) and is the most common motor neuron disease (Rechtmann et al., 2015). It causes a selective loss of upper motor neurons (UMN) of the motor cortex and lower motor neurons (LMN) of the brainstem and spinal cord (Brown and Al-Chalabi, 2017; Valko and Ciesla, 2019).

Patients with ALS develop weakness, muscle denervation, atrophy and progressive paralysis of all muscles (bulbar and respiratory), dysphagia (Al-Chalabi and Hardiman, 2013; D’Amico et al., 2013; Gowland et al., 2019) and respiratory muscle weakness that leads to respiratory failure and death (Sferrazza-Papa et al., 2018). The survival rate is 3–5 years after the onset of symptoms (Andersen, 2006; Gordon, 2013; Coan and Mitchell, 2015; Wier et al., 2019).

The incidence and prevalence of ALS vary according to the geography and design of the study (Marin et al., 2017; Kaye et al., 2018) and there are differences between African–American and Hispanic populations (Gordon et al., 2013). The incidence is 2–3 cases for every 1.000.000 inhabitants/year and prevalence of 4.6 – 5 for every 100.000 inhabitants in Western European countries (Chiò et al., 2013; Talbot, 2016). A significant increase in the overall prevalence of ALS to 8.58 cases per 100.000 people is expected by the year 2020 and to 9.67 per 100,000 people by 2116. In the United Kingdom prevalence in the 2010 year was 1415 cases and is projected to increase to 1701 by 2020 and 2635 by 2116 (Gowland et al., 2019).

ALS typically occurs in white adults between the ages of 50–60 (Chiò et al., 2013; Mehta et al., 2018), and cases in children are very rare (Martin, 2010; Bäumer et al., 2014; Ingre et al., 2015). The age of onset is earlier in men than in women and men are more prone to spinal involvement, whereas bulbar involvement is more common in women (McCombe and Henderson, 2010).

ALS is classified into two types: familial ALS (fALS) and sporadic ALS (sALS). fALS represents approximately 5–10% of the cases and is related to heterogeneous mutations of a set of genes with an autosomal dominant inheritance pattern (Mitchell and Borasio, 2007). Up to 20% of cases of fALS is due to a mutation of the gene that encodes the enzyme Cu-Zn superoxide dismutase (SOD1). sALS occurs in up to 90–95% of the cases but its origin is still unknown (Martin, 2010; Andersen and Al-Chalabi, 2011; Pan et al., 2012). fALS and sALS can affect any voluntary muscle but their presentation, phenotype and progression are variable (Wei et al., 2019), hindering differential diagnosis (Swinnen and Robberecht, 2014; Ghasemi, 2016; Van Es et al., 2017). ALS may manifest double onset: involvement of the extremities (80% of cases) or bulbar involvement (20% of cases) (Parakh et al., 2013).

The death of motor neurons results in a characteristic clinical feature: spasticity, muscular weakness and atrophy, hyperreflexia, cramps, fasciculation, Babinski sign, loss of coordination, paralysis of voluntary musculature, dysphagia and difficulties in swallowing, speech and respiration (Weiduschat et al., 2014; Zufiría et al., 2016; Solleiro-Villavicencio and Rivas-Arancibia, 2018). It is associated with metabolic disorders such as weight loss, hypermetabolism and hyperlipidemia (Dupuis et al., 2011). fALS and sALS do not affect the senses (sight, smell, taste, hearing and touch) (Fiala et al., 2013).

Several factors have been identified related to the pathogenesis of ALS: OS, mitochondrial dysfunction, neuroinflammation, excitotoxicity due to an increase in the neurotransmitter glutamate, defect in axonal transmission and in the metabolism of RNA, apoptosis, cytoskeletal abnormalities, disruption of membrane trafficking, endoplasmic reticulum stress, protein misfolding and aggregation (Papadimitriou et al., 2010; Blokhuis et al., 2013; Peters et al., 2015; Bond et al., 2018; Yusuf et al., 2018) and cysteine modifications like oxidation or palmitoylation that contribute to a general aberration of cysteine residues proteostasis (Valle and Carrì, 2017). A relationship has been established between environmental conditions and the epidemiology of ALS: alcohol, tobacco, sedentary lifestyle, fungal and viral infections or exposure to electromagnetic radiation (Yu et al., 2014).

There are currently no effective treatments for ALS and therapy is limited to symptomatic and palliative treatment (Bhattacharya et al., 2019). Riluzole (Miller et al., 2012) and edaravone (Rothstein, 2017) are the only approved pharmacological therapies that increase the survival rate by 2–3 months (Dorst et al., 2017; Hodgkinson et al., 2018), but edaravone is only beneficial to a subset of people with early stage ALS (Abe et al., 2017). Other therapeutic routes indicate multidisciplinary treatment involving: nurses, dieticians, nutritionists, occupational therapists, physical therapists, psychologists, social workers and speech therapists (Gordon, 2013).

Oxidative Stress and Amyotrophic Lateral Sclerosis

Presence of OS biomarkers and high levels of ROS have been determined in the CNS regions specifically in ALS patients (Golenia et al., 2014), which indicates that impaired redox homeostasis is a relevant factor and associated with the development and progression of neurodegeneration in fALS and sALS (Carrì et al., 2015; Petrov et al., 2017; Smith et al., 2017). High levels of certain types of ROS (H₂O₂ and O) have been observed in affected cells (Beal et al., 2005).

Loss of oxidative control and excessive ROS production are particularly linked to the mutated forms of SOD1 (Ferri et al., 2006; Hooten et al., 2015; Angelova and Abramov, 2018), which can have up to 150 different types of mutations (Gamez et al., 2006; Al-Chalabi et al., 2013). SOD1 is an antioxidant enzyme that catalyzes the conversion of O into H₂O₂ and O₂, and is key in the regulation of OS, cell damage (Mattiazzi et al., 2002; Li et al., 2011; Pehar et al., 2014), energy metabolism and cellular respiration (Saccon et al., 2013). Oxidation and/or misfolding of SOD1 results in a deterioration in the regulation of the above processes, mitochondrial dysfunction and increase in the production of superoxides (Israelson et al., 2010; Pickles et al., 2013, 2016; Richardson et al., 2013). Its mutation predisposes cellular organelles to oxidative damage (Deng et al., 2006; Ahtoniemi et al., 2008) and excessive levels of ROS that attack astrocytes (Islam, 2017). OS contributes to the aggregation of SOD1 (Brujin et al., 2004) enhancing mitochondrial dysfunction (Liu et al., 2004; Vijayvergiya et al., 2005).

The transgenic mouse model of ALS (SOD1^G93A) has enabled the identification of pathogenic mechanisms and the establishment of a “vicious cycle” between: OS, mitochondrial dysfunction and deterioration of the ETC (Jung et al., 2002; Menzies et al., 2002; Pfohl et al., 2015; Xiao et al., 2018). Most of the oxidative species that are formed in the CNS are secondary to oxidative phosphorylation (Brookes et al., 2004; Balaban et al., 2005; Karam et al., 2017) and mitochondrial dysfunction is the largest source of ROS production, so is a clear sign of affectation of motor neurons in the spinal cord and the motor cortex (Bendotti et al., 2001; Kawahara et al., 2004; Loizzo et al., 2010; Cozzolino and Carrì, 2012). Mitochondrial damage causes an alteration in intracellular calcium levels and in normal functioning of the ETC (Bond et al., 2018) that contributes to the increase of ROS and to the activation of chain reactions that lead to greater oxidative damage, reinforcing the “vicious cycle” (Harraz et al., 2008; Federico et al., 2012; Rojas et al., 2015; Loeffler et al., 2016; Van Horssen et al., 2017) and increasing cellular susceptibility to apoptosis (Guegan et al., 2001; Iverson and Orrenius, 2004).

Changes in antioxidant defense markers have been observed in patients with ALS (Cova et al., 2010). However, the results are random, due to the wide heterogeneity, form of presentation and variability of the pathogenic mechanisms of the disease (Johnson et al., 2012). Low levels of reduced glutathione (GSH) in erythrocytes (Babu et al., 2008) and in the motor cortex (Ikawa et al., 2015) of patients with ALS, a systemic pro-inflammatory state (increased levels of IL-6 and IL-8) and an impaired antioxidant system (Ehrhart et al., 2015) have been highlighted. One study compared in vivo levels of GSH in the motor cortex of 11 ALS patients with those in 11 age-matched healthy volunteers and determined that GSH levels were 31% lower in ALS patients than in healthy volunteers (Weiduschat et al., 2014). Also, decreased glutathione levels caused motor neuron degeneration in the hSOD1^wt over-expressing mice model (hemizygous mice over-expressing wild-type hSOD1 at moderate levels) (Killoy et al., 2018) and accelerated motor neuron death in SOD1^G93A mice (Pehar et al., 2014). Catalase (CAT) activity is decreased in erythrocytes of sALS patients (Nikolic-Kokic et al., 2006; Babu et al., 2008) and is significantly decreased compared to neurologically healthy controls (Golenia et al., 2014).

Studies conducted in vitro indicated that oxidative damage to nerve cells (astrocytes and oligodendrocytes) was related to neurodegeneration (Pollari et al., 2014). Oxidative imbalance decreases the number of glial cells and the ability to transmit the axonal signal (Park et al., 2007).

Markers for OS have been determined in the cerebrospinal fluid (CSF), tissues, blood and urine of patients with ALS (Blasco et al., 2017). After postmortem analysis of neuronal tissues in sALS and fALS patients, an increase of OS biomarkers was noted in proteins, lipids and DNA (Beal, 2002; Agar and Durham, 2003; Kim et al., 2003; Turner et al., 2013; Bozzo et al., 2016). The most frequently studied biomarkers include: carbonylated and/or glycosylated proteins, lipid peroxidation and DNA damage (Shibata et al., 2002).

In the nervous tissues of ALS patients, high levels of carbonylated proteins have been measured in the motor cortex (Sasaki et al., 2000; Guareschi et al., 2012; Tan et al., 2014) and high levels of advanced products of protein oxidation in the plasma of the erythrocytes of sALS patients (LoGerfo et al., 2014). In ALS-mouse models, non-functional proteins secondary to the oxidation of amino acid residues by peroxynitrite have been observed (Yoshino and Kimura, 2006). In addition, oxidative damage results in the aggregation of TDP-43, the major disease-associated protein involved in the pathogenesis of ALS (Moujalled et al., 2017; Oberstad et al., 2018) that promotes OS in neuronal cells (Duan et al., 2010; Cohen et al., 2012, 2015; Magrané et al., 2014) (Figure 1).

CNS lipids are susceptible to oxidative damage (Niki, 2014) and lipoperoxidation generates high levels of HNE, MDA (Radak et al., 2011) and F2-isoprostane (F2-IsoPS) (Milne et al., 2007; Milatovic et al., 2011; Van’t Erve et al., 2017) (Figure 1). In the CSF of patients with ALS, high levels of HNE and 3-nitrotyrosine (3-NT) have been obtained (Simpson et al., 2004; Duffy et al., 2011; Perluigi et al., 2012; Ayala et al., 2014; Santa-Cruz and Tapia, 2014).

The guanine contained in DNA is highly susceptible to oxidation and acts as a target for ROS (Lee et al., 2007; Chang et al., 2008). 8-oxo-deoxyguanosine (8-OHdG) can be considered as a specific biomarker of oxidation of the motor cortex in ALS (Cooke et al., 2000, 2002; Ihara et al., 2005; Mitsumoto et al., 2008) (Figure 1). Increased levels of 8-OHdG and isoprostanoids have been observed in the urine of subjects affected by the disease compared to the control group (Miller et al., 2014).

The evaluation of GPx activity, glutathione reductase (GR), SOD, total serum antioxidant status (TAS), MDA and 8-OHdG in ALS patients, found a significant decrease in TAS levels and an increase of 8-OHdG and MDA levels, together with significantly higher oxidized/reduced glutathione (GSSG/GSH) ratio and IL-6 and IL-8 (Blasco et al., 2017).

Antioxidants and Amyotrophic Lateral Sclerosis

The evidence implicates free radicals and OS as factors related to the pathogenesis of ALS. Interest has focused on substances with antioxidant potential such as: vitamin E, carotenes, flavonoids, resveratrol, epigallocatechin gallate, curcumin, Co-enzyme Q10, melatonin and edaravone as useful agents in the management of this disease (Table 1).

Vitamin E

Vitamin E (α-tocopherol) is one of the most studied lipophilic antioxidants due to its ability to cross the cell membrane and the protection that it provides against lipoperoxidation (Butterfield et al., 2002; Di Matteo and Esposito, 2003), ROS and RNS (Barber and Shaw, 2010) (Table 1). The studies on nutritional supplementation with this vitamin have obtained contradictory results.

This antioxidant has been associated with a delay in the clinical onset of the disease (Table 1) in transgenic mice that express mutant copies of the gene encoding SOD1 (an animal model of ALS) (Gurney et al., 1996). Measurements of the erythrocyte activity of the three main radical scavenging enzymes (SOD1, CAT, and GPx) indicated that vitamin E supplementation (300–3000 U/day) in 14 ALS patients did not affect the activity of the three enzymes (Przedborski et al., 1996). One study showed an accumulation of vitamin E in the spinal cord and increased MDA levels over the lifetime of the mouse compared to non-transgenic mice (Hall et al., 1998).

In a double-blind placebo-controlled randomized clinical trial, vitamin E did not appear to affect survival and motor function in ALS. However, after 3 months of treatment with vitamin E and riluzole, an increase in plasma GSH levels (Table 1) and a decrease in plasma thiobarbituric acid reactive species (TBARS) levels were observed, markers typically altered in the plasma of the patients with ALS (Desnuelle et al., 2001). Vitamin E was associated with a slower progression of ALS (Orrell et al., 2004) and in one study it was observed that regular use of vitamin E supplements was associated with a lower risk of dying by ALS (Ascherio et al., 2005) (Table 1).

Other similar studies did not detect significant differences between placebo and the group treated with α-tocopherol and indicated that there are insufficient results to claim that megadoses with vitamin E are effective in slowing the progression of the disease (Graf et al., 2005). Supplementation with 600 mg/day of vitamin E did not show differences with respect to the placebo group (Galbussera et al., 2006). In a case-control study with 132 patients suffering from ALS, a significant decrease in the risk of the disease (Table 1) was observed when the intake of vitamin E was higher than the average (Veldink et al., 2007). Supplementation with vitamin E over a prolonged period was associated with lower ALS rates (Wang H. et al., 2011) and a study that included 50 cases of male ALS patients concluded that in men with baseline serum α-tocopherol below the average, there was a non-significant decrease in ALS risk in those receiving α-tocopherol supplementation (50 mg/day) compared to those not receiving α-tocopherol. If baseline serum α-tocopherol was above the average, α-tocopherol supplementation had no effect on the risk of ALS. In this case, α-tocopherol supplementation did not have a significant protective effect on ALS risk (Michal-Freedman et al., 2013).

Carotenes

Carotenes are natural pigments, responsible for the orange, red (Krinsky and Johnson, 2005), yellow or green color of fruits and vegetables (Guest and Grant, 2016) with antioxidant and neutralizing properties against ROS (Fiedor et al., 2012; Nisar et al., 2015) (Table 1).

There is a beneficial association between ALS and the intake of carotenes (Okamoto et al., 2009; Nieves et al., 2016). Thus, their consumption could help the prevention and/or delay the onset of ALS (Fitzgerald et al., 2013) (Table 1) but in a case-controlled study with 77 Koreans diagnosed with ALS, it was determined that dietary intake of carotenes was negatively associated with ALS (Jin et al., 2014). A study conducted in 5 cohorts determined that a higher intake of these pigments was associated with a reduced risk of ALS and that high dietary intakes of ß-carotene and lutein were inversely associated with the risk of suffering from this disease. Astaxanthin and lycopene have shown a beneficial effect in ALS (Longecker et al., 2000; Isonaka et al., 2011) but in a study with the SOD1^G93A mice model of ALS, a tomato-enriched food (rich in lycopene) did not affect disease onset and survival (Esposito et al., 2007). β-carotene could serve as a potential therapeutic molecule for treating neuroinflammation and apoptosis in ALS patients (Krishnaraj et al., 2016) (Table 1).

Flavonoids

Flavonoids are natural substances mainly present in fruits and vegetables (He et al., 2017) that have a protective effect against ROS (Cao et al., 1997), modulate the activity of different metabolic pathways (Mansuri et al., 2014) (Table 1) related to the reduction of cognitive damage and neuronal dysfunction (Vauzour et al., 2008) and suppress neuroinflammation (Solanki et al., 2015).

7,8-dihydroxyflavone (7,8-DHF) has neuroprotective and regulatory properties on neuromuscular transmission (Mantilla and Ermilov, 2012). Chronic administration of 7,8-DHF significantly improved motor deficits and enhanced lower neuronal survival in the transgenic ALS mouse model (Korkmaz et al., 2014) (Table 1).

Treatment with fisetin reduced intracellular ROS levels, motor neuron loss and improved motor activity and survival rate in three different hSOD1-related mutant models of ALS (Drosophila expressing hSOD1^G85R, hSOD1^G93ANSC34 cells and transgenic mice hSOD1^G93A) (Wang et al., 2018) (Table 1).

Quercetin is an abundant flavonoid in the diet (onion, apple, broccoli and berries) (Esposito et al., 2002) that has been shown to reduce mitochondrial damage in various animal models of OS. Treatment with quercetin could be a therapeutic strategy for attenuating neuronal death against aluminum-induced neurodegeneration in the rat hippocampus (Sharma et al., 2016). Quercetin and its derivative, quercetin 3-β-D-glucoside (Q3BDG), could be therapeutic inhibitors of the aggregation and misfolding of SOD1 associated with ALS (Ip et al., 2017) (Table 1).

Resveratrol

Resveratrol (RES) can interact with mutant SOD1 (G93A) protein (a distinctive feature of ALS) (Julien, 2007; Srinivasan and Rajasekaran, 2018; Laudati et al., 2019) and has positive effects by up-regulating sirtuin 1 (SIRT1) expression in the mutant hSOD1-G93A-bearing motor neuron-like cell culture model of ALS (Wang J. et al., 2011) (Table 1). It delays the onset of ALS, increases the survival of spinal motor neurons, preserves the function of the lower and upper motor neuron (Mancuso et al., 2014a, b), attenuates the loss of motor neurons and improves muscle atrophy and mitochondrial function of muscle fibers in a SOD1^G93A mouse model of ALS (Song et al., 2014) (Table 1). One study showed that bone marrow mesenchymal stem cells from ALS patients showed down-regulation of AMPK/SIRT1 signaling, which was recovered by treatment with RES (Yun et al., 2019) (Table 1).

Epigallocatechin Gallate

Epigallocatechin gallate (EGCG) is a catechin present in green tea (Chung et al., 2010) and to which an antineurodegenerative and antioxidant effect is attributed (Nie et al., 2002; Panickar et al., 2009), especially on the motor neurons (Koh et al., 2006) because it crosses the blood-brain barrier and modulates mitochondrial responses to OS (Bedlack et al., 2015) (Table 1). It also protects against lipoperoxidation (Table 1) in in vitro studies by exposing ROS to the phospholipids of the cell membrane bilayer (Terao et al., 1994). It prevents OS-induced death of mutant SOD1 motor neuron cells by alteration of cell survival and death signals (Koh et al., 2004). Treatment with EGCG could delay the outbreak or progression of ALS through changes in intracellular signals, increases survival signals (like PI3-K and Akt) and reduces death signals (like GKS-3ß, cytosolic cytochrome c, activated caspase-3 and cleaved poly ADP-ribose polymerase) (Levites et al., 2002; Mandel et al., 2003, 2005; Koh et al., 2006) (Table 1). Oral administration of 10 mg/kg of EGCG from a presymptomatic stage delays the onset of the disease and prolongs useful life, in addition to increasing the number of motor neurons, decreasing the activation of the microglia, reducing the concentration of NF-kB, caspase-3 and iNOS in a transgenic mouse model of ALS (Xu et al., 2006) (Table 1).

Curcumin

Curcumin is a natural and liposoluble dye obtained from turmeric (Table 1). It has neuroprotective effects and provides protection against OS (Kim et al., 2012), mitochondrial dysfunction, inflammation and protein aggregation (Ullah et al., 2017; Rakotoarisoa and Angelova, 2018; Ghasemi et al., 2019).

Curcumin activates nuclear factor erythroid 2-related factor (Nrf2) target genes in primary spinal cord astrocytes, decreases the level of intracellular ROS and attenuates oxidative damage and mitochondrial dysfunction (Jiang et al., 2011) (Table 1). It eliminates the excitability induced by TDP-43 (the major pathological protein in sporadic ALS) in a motor neuron-like cellular model of ALS (Mackenzie and Rademakers, 2008; Dong et al., 2014). Dimethoxy curcumin (DMC) could decrease mitochondrial dysfunction in mutated TDP-43 stably transfected cell lines (Lu et al., 2012) (Table 1). It binds to the pre-fibrillar aggregates of SOD1, altering its amyloidogenic pathway and decreasing cytotoxicity (Bhatia et al., 2015). Curcumin may improve survival in patients with ALS, especially those with bulbar involvement (Ahmadi et al., 2018). In a double-blind therapeutic trial, treatment with curcumin showed a decrease in ALS progression and a reduction of oxidative damage (Chico et al., 2018) (Table 1).

A study indicates that a drug delivery system based on curcumin will be proposed for the treatment of ALS (Tripodo et al., 2015) but others indicate that the use of curcumin as therapy in ALS has disadvantages: chemical instability and low oral bioavailability and water solubility rate (Rakotoarisoa and Angelova, 2018) (Table 1). Therefore, it is necessary to develop new technologies to overcome these limitations (Liu et al., 2016).

Co-enzyme Q10

Co-enzyme Q10 (CoQ10) is an endogenous antioxidant and a cofactor in the ETC (Petrov et al., 2017) involved in redox balance (Yamamoto, 2016) (Table 1). In the SOD1 transgenic mouse model of ALS, supplementation with CoQ10 extended survival by 6 days and increased brain mitochondrial concentration compared to controls (Matthews et al., 1998; Strong and Pattee, 2000; Beal, 2002) (Table 1). After comparing the plasma redox status of CoQ10 in 20 sALS patients with those in healthy age/sex-matched controls, a significant increase in the oxidized form of CoQ10 in sALS was observed (Sohmiya et al., 2005). A study conducted on 31 subjects, showed that treatment with megadoses of 3000 mg/day of CoQ10 over 8 months could improve mitochondrial dysfunction in ALS (Ferrante et al., 2005). However, one study suggested that serum CoQ10 concentrations are unrelated to the risk of ALS (Molina et al., 2000; Kaufmann et al., 2009).

Melatonin

Melatonin is an amphiphilic molecule that has been identified as a potent antioxidant therapeutic agent in neurodegenerative diseases (Polimeni et al., 2014) associated with mitochondrial dysfunction (Ganie et al., 2016) (Table 1). A study indicated that melatonin could be a candidate for neuroprotection in ALS (Jacob et al., 2002). In the SOD1^G93A transgenic mouse model of ALS, high doses of melatonin administered orally delayed the progression of the disease and increased the survival rate (Weishaupt et al., 2006; Zhang et al., 2013) (Table 1). However, evidence suggests that intraperitoneal melatonin is not neuroprotective and may exacerbate neurodegeneration (Dardiotis et al., 2013). Clinical trials employing melatonin in the range of 50–100 mg/day are required before its relative merits as a neuroprotective agent are definitively established (Pandi-Perumal et al., 2013). Recent studies suggest that riluzole but not melatonin ameliorates acute motor neuron degeneration and moderately inhibits SOD1-mediated excitotoxicity induced disrupted mitochondrial calcium signaling in ALS (Jaiswal, 2017).

Edaravone

Edaravone is a low-molecular-weight antioxidant drug (Radicava^®), administered intravenously (Petrov et al., 2017) which acts as a free radical scavenger (Jackson et al., 2019) (Table 1). In 2015, edaravone was approved for ALS treatment in Japan (Okada et al., 2018) and by the Food and Drug Administration of United States in 2017 (Watanabe et al., 2018).

Edaravone easily crosses the blood-brain-barrier and displays a high brain penetration capacity (Jin et al., 2017). Its amphiphilic capacity allows edaravone to scavenge both lipid and water soluble peroxyl radicals and chain-carrying lipid peroxyl radicals (Nagase et al., 2016) (Table 1).

The antioxidant mechanisms of edaravone are: enhancement of prostacyclin production, hydroxyl radical trapping and quenching of active oxygen (Sawada, 2017) (Table 1). Edaravone eliminates lipid peroxides and hydroxyl radicals during cerebral ischemia, protects nerve cells within or around the ischemic region from free radical damage (Abe et al., 2014), ameliorate OS and suppress degeneration of spinal motor neurons (Ikeda and Iwasaki, 2015). It is attributed anti-inflammatory (Bailly, 2019) and protective effects in neurons, microglia, astrocytes and oligodendrocytes (Banno et al., 2005; Miyamoto et al., 2013) (Table 1).

Investigation of the safety and efficacy of edaravone in 20 ALS patients who received this antioxidant intravenously indicated that this drug is safe and may delay the progression of functional motor disturbances by reducing OS (Yoshino and Kimura, 2006) (Table 1).

Nicotinamide Riboside and Neurodegenerative Diseases

NAD⁺ Role and Levels

NAD⁺ is a coenzyme that takes part in critical redox reactions (its reduced form is NADH) for the operation of mitochondrial metabolism (Berger et al., 2004; Yoshino et al., 2018). Is an important biological mediator due to its many essential functions for survival: redox reactions, signaling pathways, energy metabolism, mitochondrial function, calcium homeostasis, DNA repair, gene expression (Guarente, 2014; Yaku et al., 2018), brain metabolism, neurotransmission, learning, memory, axonal neuroprotection (Araki et al., 2004; Conforti et al., 2006; Gong et al., 2013) and participation in the NAD⁺/PARP/SIRT1 axis related to aging (Mendelsohn and Larrick, 2017) (Figure 2).

FIGURE 2

NAD⁺ can act as a cosubstrate for sirtuins (SIRT) (Verdin, 2015), class III histone deacetylase enzymes whose activity is dependent on NAD⁺ levels (Tang, 2016; Jęśko et al., 2017) and for poly(ADP-ribose) polymerases (PARPs), a family of proteins essential for repairing DNA damaged by ROS (Shen et al., 2015) (Figure 2).

Sirtuins are related to the metabolic status of cells and are key in cellular metabolism, regulation of the expression of certain genes (O’Callaghan and Vassilopoulos, 2017), energy and mitochondrial metabolism (Covington and Bajpeyi, 2016), inflammation and DNA repair (Tang, 2017). They can be found in the cytoplasm, nucleus and mitochondria (Kupis et al., 2016). In neurodegenerative diseases and in aging they organize the response to OS and damage to DNA and are related to the functionality of the respiratory machinery and the production of ROS in different tissues (Huang et al., 2010).

Activation of SIRT increases resistance to OS (Haigis and Sinclair, 2010) through an increase in metabolic pathways responsible for the detoxification of ROS (Salvatori et al., 2017) such as superoxide dismutase 2 (SOD2), isocitrate dehydrogenase 2 (IDH2) and CAT (Tennen and Chua, 2011). They improve metabolic capacity, promote mitochondrial oxidative metabolism and facilitate repair of DNA damage (Haigis and Sinclair, 2010) (Figure 2).

SIRT1 acts on the pathway of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) (Alquilano et al., 2013; Tang, 2016), a fundamental regulator of energy metabolism (Bayer et al., 2017; Thirupathi and de Souza, 2017) and mitochondrial dynamics (Singh et al., 2016) associated with an increase in antioxidant defenses through SOD2 and GSH (Liang and Ward, 2006; Zhong and Xu, 2008; Wang et al., 2015) (Figure 2). Reduction of SIRT1 activity compromises oxidative metabolism and antioxidant capacity, affecting complex I of the ETC, mitochondrial function and biogenesis (Rodgers et al., 2005). This effect has been observed in aging and different pathologies: neurodegenerative diseases, metabolic disorders and cancer (Rass et al., 2007; Hou et al., 2017b; Jęśko et al., 2017). In ALS, alterations in SIRT1 levels have been determined in postmortem tissues from patients (Körner et al., 2013) and in mouse models of ALS (Han et al., 2012).

Sirtuin 3 (SIRT3) regulates mitochondrial function and the aging processes (Buck et al., 2017) by activating SOD2 and CAT (Salvatori et al., 2017) that are involved in the detoxification of ROS (Qiu et al., 2010; Kida and Goligorsky, 2016) (Figure 2).

The decrease in NAD⁺ levels may be secondary to a defect in its biosynthesis or to depletion (Imai and Guarente, 2014) and leads to a deficiency in the activities of SIRTs in the nucleus and mitochondria (Chang and Guarente, 2013; Gomes et al., 2013; Mendelsohn and Larrick, 2014; Frederick et al., 2016), reduces the mitochondrial unfolded protein response (Mendelsohn and Larrick, 2017), disrupts ATP biosynthesis, decreases the ability to pump calcium against the intracellular gradient (Camandola and Mattson, 2011), disrupts calcium homeostasis, increases excitotoxicity (Rzheshevsky, 2014) and has deleterious effects on muscle health (Goody and Henry, 2018).

The lower bioavailability of NAD⁺ levels is involved in many diseases such as neurodegenerative pathologies (Essa et al., 2013; Johnson and Imai, 2018) and affects the production of energy, lowers the levels of ATP and limits the protection of SIRT1 (Houtkooper et al., 2010; Cantó et al., 2012; Imai and Guarente, 2014), an aspect that could worsen in these diseases because of its progressive nature (Cantó et al., 2015). NAD⁺ levels have been shown to decrease with age, leading to low levels in the brain (Zhu et al., 2015). Several studies have demonstrated that NAD⁺ metabolism is involved in neuronal function and in the pathophysiology of neurodegenerative diseases (Hikosaka et al., 2019) and that NAD⁺ levels in tissues can produce beneficial therapeutical effects in this type of diseases (Aman et al., 2018; Kulikova et al., 2018).

The activation of metabolic pathways related to mitochondria and the production of energy through the NAD⁺ and SIRT1 is currently suggested as a therapeutic strategy (Yang and Sauve, 2016; Tang, 2017; Rajman et al., 2018; Zhang and Sauve, 2018).

Recovery and/or increase of NAD⁺ levels can protect skeletal muscle from progressive deterioration (Fletcher et al., 2017), reverse the damage to cerebral energy metabolism, increase the protection against OS (López-Otín et al., 2013; Brown et al., 2014; Verdin, 2015), promote the activity of SIRTs and proteins involved in mitochondrial function (Bonkowski and Sinclair, 2016), confers resistance against peroxide toxicity, decreases mitochondrial ROS (Harlan et al., 2016), protection against neurodegeneration (Sasaki et al., 2006) and upkeep of dependent enzymes that are involved in synaptic plasticity and neuronal stress resistance (Lautrup et al., 2019).

Therefore, the repletion of NAD⁺ levels using precursors can ameliorate this age-associated functional defects (Imai and Guarente, 2014), helping to reverse the pathogenic processes characteristic of neurodegenerative diseases (Zhang et al., 2016).

Precursors of NAD⁺

The precursors of NAD⁺ include nicotinamide mononucleotide (NMN), nicotinamide (NAM), nicotinic acid (NA) and nicotinamide riboside (NR) (Harlan et al., 2016). Most of the NAD⁺ precursors are more stable and have higher ability to enter neurons than NAD⁺ (Sasaki et al., 2006). NMN and NR are the most used and both have shown an increase in NAD⁺ levels in the cell (Nikiforov et al., 2011) (Table 2). Most evidence concludes that NR has a greater ability to stimulate a significant increase in NAD⁺ levels (Cantó et al., 2012) and advantages over the use of other precursors (Table 2).

NA prevents Pellagra (Prousky et al., 2011) and has positive effects on the regulation of lipids (total cholesterol, triglycerides and LDL) (Guille et al., 2008) (Tabla 2). However, produces cutaneous flushing and does not work as NAD⁺ precursor in the majority of cells (Davidson, 2008) (Table 2). One of the most important advantages of NR over NA is that supports neuronal NAD⁺ synthesis (Bogan and Brenner, 2008) and has action on several types of cultured mammalian cells, including mouse and human cells (Yang H. et al., 2007) (Table 2).

There is no consensus on how NMN is transported to the cell (Grozio et al., 2019; Schmidt and Brenner, 2019) (Table 2). However, NR is five times more effective than NMN in increasing intracellular NAD⁺ levels in skeletal muscles (Oakey et al., 2018) (Table 2).

After comparing NR with NA and NAM in mice, NR showed a significant higher peak of NAD⁺ concentration and a significant increase of intermediate NAD⁺ precursors including NMN, NA mononucleotide and NA adenine dinucleotide (Trammell et al., 2016) (Table 2). NR has a different time course compared to NAM and NA and produces more NAD⁺ than the other precursors in equivalent doses (Trammell et al., 2016). NR increases the ratio of NAD⁺/NADH more significantly compared NMN, NAM and NA and this can contribute to improving the oxidative capacity of mitochondria (Cantó et al., 2012) and to decrease the rate of oxidative damage against DNA and mitochondrial stress (Ramamoorthy et al., 2012; Srivastava, 2016; Dolopikou et al., 2019) (Table 2).

NR is a nucleoside that incorporates a nicotinamide and a ribose (Belenky et al., 2007; Chi and Sauve, 2013) group. It is a trace nutrient known as vitamin B3 (Lanska, 2012), available in certain foods (dairy products, fish, eggs, and vegetables) (Minto et al., 2017), nutritional supplements and fortified foods (Colbourne et al., 2013). Its effects are associated with energy metabolism and neuroprotection (Chi and Sauve, 2013). When the NR enters the cells it is converted to NAD⁺ by at least two types of metabolic pathway. The first requires the participation of the nicotinamide riboside kinases (NRKs) (Chi and Sauve, 2013) in two of its isoforms (NRK1 and NRK2) (Bieganowski and Brenner, 2004) and the second requires the action of purine nucleoside phosphorylase (PNP) and nicotinamide phosphoribosyltransferase (NAMPT) (Burgos et al., 2013) (Figure 2).

The conversion of NR into NAD⁺ has been observed in animal tissues of muscle and brain (Chi and Sauve, 2013) and treatment by exogenous supplementation of NR is able to increase intracellular concentrations of NAD⁺ and promote its beneficial effects (Braidy et al., 2008) (Figure 2). NR enhances protection against aging and related diseases, with positive results on longevity in multiple animal models (Mouchiroud et al., 2013; Poljsak and Milisav, 2016) and has been recently reported that NR protects against excitotoxicity induced axonal degeneration (Vaur et al., 2017). The increase of NAD⁺ levels by supplementation with precursors such as NR improves mitochondrial and muscular function and the function of neuronal cells in mice (Mendelsohn and Larrick, 2017). A study performed in mice supplemented nutritionally with 400 mg/kg/day of synthetic NR showed an increase in NAD⁺ levels in muscle and liver tissue (Cantó et al., 2012). As NR increases the NAD⁺/NADH ratio, it could be related to an improvement of the oxidative capacity of the mitochondrial pathway and could be a therapeutic strategy of interest in those diseases that are associated with mitochondrial dysfunction and OS such as neurodegenerative diseases (Cantó et al., 2012). Improvement of NAD⁺ levels provides greater mitochondrial resistance against OS (Yang T. et al., 2007) and prevents cell death due to the protective function of SIRT3 (Hafner et al., 2010), which stimulates SOD, responsible for enhancing the “detoxification” of ROS (Chen et al., 2011) (Figure 2).

Supplementation with NR is safe in mice and humans and has minimal toxicity, high bioavailability and high capacity to cross the blood-brain barrier (Trammell et al., 2016; Airhart et al., 2017; Martens et al., 2018) (Table 2).

Nicotinamide Riboside

Neurodegenerative diseases are associated with a progressive decrease in muscle mass and strength and an increase in their weakness (González et al., 2017; Van Damme et al., 2017; Dahlqvist et al., 2019). Muscle contractility dysfunction precedes the loss of motor unit connectivity in the SOD1^G93A mouse model of ALS (Wier et al., 2019) with neurodegeneration being one of the determinant risk factors for muscle quality (Di Pietro et al., 2017; Moon et al., 2018). Treatment with NR improves muscle function in aged mice (Cantó et al., 2012) and has benefits on muscle strength and skeletal muscle resistance in knock out mice that have specific elimination of NAMPT and a decrease of 85% in the intramuscular content of NAD⁺ (Frederick et al., 2016). This would indicate that the maintenance of NAD⁺ homeostasis is critical for muscle mass and its contractile function (Mendelsohn and Larrick, 2014; Frederick et al., 2016). NR induces rejuvenation in muscle and brain stem cells (Ryu et al., 2016) and an increase in neurogenesis and muscle function (Zhang et al., 2016). NAD⁺ is a fundamental modulator of muscle senescence and after treatment with NR, there is an acceleration of muscle regeneration in both young and old mice and an improvement in running times, maximum distances, grip strength of the extremities of aged mice and increased expression of cell cycle genes (Zhang et al., 2016).

Levels of PGC-1α are decreased in Alzheimer’s disease (AD) and this is related to the formation of ß-amyloid plaques and greater deposition of this substance (main characteristics of AD) (Wu et al., 2006; Quin et al., 2009). Studies conducted in animal models of AD established a relationship between the levels of NAD⁺ and a decrease in the toxicity of the amyloid substance (Kim et al., 2007; Quin et al., 2009). For this reason, the therapeutic strategy based on nutritional supplementation with NR could be of interest in AD cases to stop the onset and progression of the dementia (Rodgers et al., 2005) and to improve cognitive function and synaptic plasticity by promoting the function of PGC-1α as demonstrated in Tg2576 mice (mouse model of ALS) (Gong et al., 2013). After analyzing the effect of NR on the physiopathology and cellular mechanisms in the 3xTgAD/Polß^± mouse model (mice deficient in DNA repair that exacerbates the main characteristics of AD in humans) it was observed that supplementation with NR significantly increased the NAD⁺/NADH ratio, reduced neuroinflammation, apoptosis and damage to DNA, increased neurogenesis, restored synaptic plasticity, improved learning capacity and reversed memory deficits (Hou et al., 2017a). Treatment with NR improves cognition in transgenic mice with AD by reducing the phosphorylation of the Tau protein (pTau) (a form that accumulates in the brain of AD patients and is the hallmark of the disease) (Green et al., 2008; Rüb et al., 2017; Nizynski et al., 2017). In the case of PD, the repletion of NAD⁺ through the use of NR prevents aging related to the loss of dopaminergic neurons and the reduction of motor function in Drosophila fly model of PD (Sidransky et al., 2009). NR improves mitochondrial function in PD neurons, increases the markers of mitochondrial biogenesis, significantly decreases the production of mtROS (mitochondrial ROS), reduces mitochondrial membrane potential and increases the levels of NAD⁺ and NADH (Schöndorf et al., 2018).

Axonal degeneration occurs in most neurodegenerative diseases (AD, PD, ALS) (Raff et al., 2002; Coleman, 2005). The increase in NAD⁺ synthesis through the use of precursors such as NR promotes axonal protection (Wang et al., 2005; Sasaki et al., 2006). Improvement of the NAD⁺ recovery pathway reverses the toxicity of primary astrocytes expressing the SOD1 mutation related to ALS, decreasing the mitochondrial production of ROS and reversing the neurotoxic effects (Harlan et al., 2016). Excitotoxicity is a process that takes place in most neurodegenerative disorders like ALS and is related to strong NAD⁺ depletion in neurons. NR protects against excitotoxicity-induced axonal generation (Vaur et al., 2017).

In Duchenne’s muscular dystrophy disease, supplementation with NR reverses progressive wear and improves resistance in skeletal muscle NAMPT in the knock out mouse model (Ryu et al., 2016).

Pterostilbene and Neurodegenerative Diseases

Polyphenols are organic metabolites present in plants (Cory et al., 2018) and widely distributed in a variety of dietary sources (Aherne and O’Brien, 2002; Kim et al., 2009): fruits, vegetables, legumes, whole grains, seeds, nuts, extra virgin olive oil, red wine, coffee, tea, chocolate, herbs and spices (Rusconi and Conti, 2010; Fu et al., 2011; Regueiro et al., 2014; Vallverdú-Queralt et al., 2014, 2015; Talhaoui et al., 2016). Despite their zero energy contribution (Ruiz et al., 2009) they act as bioactive dietary components associated with multiple positive health effects (An-Na et al., 2014; Ganesan and Xu, 2017; Szwajgier et al., 2017; Renaud and Martinoli, 2019) due to their regulating action on metabolism, chronic diseases and cell proliferation (Tressera-Rimbau et al., 2017). Polyphenols have a chemical structure with properties that make them the compounds with the greatest antioxidant action: o-diphenolic group, 2-3 double bond conjugated with the 4-oxo function and hydroxyl groups (OH) in positions 3 and 5 (Ruiz et al., 2009). They have antioxidant (Hua and Rong, 2016; Tarique et al., 2016), anti-inflammatory (Oliviero et al., 2018), anticarcinogenic (Niedzwiecki et al., 2016), antiallergic (Juríková et al., 2015), antibiotic (Xie et al., 2017), and immunomodulatory (Nour et al., 2018) properties.

Polyphenols can be a useful therapeutic strategy in pathologies that present OS such as neurodegenerative diseases (Bhullar and Vasantha, 2013; Raskin et al., 2015; Reinisalo et al., 2015; Carvalho et al., 2018), cancer and cardiovascular diseases (Crozier et al., 2009; Bulotta et al., 2014; Lamuela-Raventós et al., 2014). Taking into account that nutrition is a factor that modulates processes such as cognition or progression of CNS diseases (Gustafson et al., 2015; Huhn et al., 2015), polyphenols have recently been associated with: prevention, repair of oxidative damage (Lange and Li, 2018), synaptic plasticity, neuronal signaling and autophagy (Miller and Shukitt-Hale, 2012; Poulose et al., 2014).

Among the polyphenols with important pharmaceutical activity are the stilbenes (Dvorakova and Landa, 2017), a group of non-flavonoid phytochemicals of polyphenolic structure with a 1,2-diphenylethylene core, which are produced naturally in plants via the phenylpropanoid pathway (Sirerol et al., 2016) to protect the plant from fungal infection and toxins (Akinwumi et al., 2018). There is a wide variety of forms because of a common structure to which various substituents can be added in different positions and they have an acidic and amphiphilic character (Neves et al., 2012). Although the trans isomer is the most common form of presentation (since it is the most stable), it can also be found in the cis isomer (Rivière et al., 2012). The following properties have been attributed to them: antioxidant, anti-inflammatory, neuroprotective, cardioprotective, anti-carcinogenic (Lange and Li, 2018), hypolipidemic and anti-diabetic (Voloshyna et al., 2013; Szkudelski and Szkudelska, 2015). They have great utility potential in the field of neurodegenerative diseases. They reduce the formation of amyloid plaques in the brain, decrease the production of ROS and could be of interest in other situations such as: ischemia-reperfusion injury, atherosclerosis, diabetes, cancer, obesity, platelet aggregation, blood pressure, depigmentation and cardiomyocyte and cardiac hypertrophy (Thandapilly et al., 2011; Gomez-Zorita et al., 2013; Zordoky et al., 2015; Guo et al., 2016; Akinwumi et al., 2018).

One of the most studied stilbenes has been Resveratrol (RES) (3,5,4’-trihydroxy-trans-stilbene), due to its benefits in cardiovascular health (Zordoky et al., 2015; Bonnefont-Rousselot, 2016; Dyck et al., 2019). However, recent studies focus their interest on pterostilbene (PTER) (trans-3,5-dimethoxy-4hydroxystilbene), a dimethylated natural stilbene (Albassam and Frye, 2019) with 1 hydroxyl group and 2 methoxy groups (Cichocki et al., 2008; Estrela et al., 2013; Traversi et al., 2016), which provides greater oral bioavailability, half-life, lipophilicity and higher permeability to targeted tissue (Kapetanovic et al., 2011; Yeo et al., 2013) with respect to RES (3 hydroxyl groups). In addition, PTER is less susceptible to phase II liver metabolism (Zhou et al., 2016). These particular characteristics improve its biological potential (Yeo et al., 2013) and its high bioavailability in vivo is an advantage over RES (Chiou et al., 2011; Carey et al., 2013; Lin et al., 2016). PTER presents a bioavailability of 80% compared to 20% for RES and plasma levels of PTER and PTER sulfate were significantly higher than plasma levels of RES and RES sulfate in a mouse model (Kapetanovic et al., 2011). After administration of PTER and RES at the same dose to male and female mice for 8 weeks, PTER reached higher concentrations in the serum and in the brain than RES (Chang et al., 2012).

The high lipophilicity of PTER allows it to easily cross the blood-brain barrier (Temsamani et al., 2015), resulting in greater neuroprotection than RES (Choo et al., 2014). In AD, PTER presents superior neuroprotection than RES (Chang et al., 2012) and is the stilbene with the highest inhibitory potential for 5-lipoxygenase (5-LOX) (Kutil et al., 2015), decreasing the levels of lipid and protein oxidation (Czpaski et al., 2012). It is a more potent anticancer and anti-inflammatory agent than RES (Chiou et al., 2011) and it distributes widely among the main target organs (brain, liver, kidney, heart and lung) for what seems to be a promising (Choo et al., 2014) and safe (Riche et al., 2013) therapeutic strategy. A study in male and female Swiss mice examined the sub-chronic toxicity and the possible adverse effects of PTER and concluded that, even with the highest dose administered, PTER was not toxic (Ruiz et al., 2009).

Molecular Mechanisms of PTER

The physiological activities of PTER include: antioxidant and anti-inflammatory activity, ability to restore intracellular calcium and cognitive function (Li Y. R. et al., 2018) (Figure 3).

FIGURE 3

Antioxidant Activity

PTER stands out for its antioxidant action against numerous types of free radicals: HO, H₂O₂ (Castellani et al., 2008; Mikstacka et al., 2010; Acharya and Ghaskadbi, 2013) and NO^∙ (Pan et al., 2008; Zhang et al., 2012). It is able to neutralize metal-induced radicals (Rossi et al., 2013; Saw et al., 2014) and to inhibit oxidation and lipoperoxidation processes (Rimando et al., 2002) causing a decrease in carbonylated proteins and oxidation by-products: MDA, HNE and 8-OHdG (Li Y. R. et al., 2018) (Figure 3). The administration of PTER improves the antioxidant defenses of the brain by raising the levels of CAT, GSH and the activity of SOD (Naik et al., 2017) (Figure 3). In addition, diet supplemented with PTER increases the expression of SOD2 (Ding et al., 2007). Pre-treatment with PTER has a potent antioxidant function that increases SOD activity in hypoxic-ischemic brain injury in the P7 rat model (Li D. et al., 2016). Treatment with PTER reduces glutamate-induced OS injury by reducing ROS and increasing the function of SOD and GSH by activating the Nrf2 signaling pathway in neuronal cells (Wang et al., 2016), a target factor for the prevention of diseases related to aging such as neurodegenerative diseases (Bhakkiyalakshmi et al., 2016; Li Y. R. et al., 2018) (Figure 3).

The potent antioxidant mechanism of PTER is associated with SIRT1 signaling activation (Li et al., 2015; Guo et al., 2016; Liu et al., 2017) leading to the attenuation of the skeletal muscle OS injury and mitochondrial dysfunction induced by ischemia-reperfusion injury in male Sprague-Dawley rats (Cheng et al., 2016). PTER acts on Nrf2 (Saw et al., 2014; Zhang et al., 2014; Xue et al., 2017) and attenuates high glucose-induced central nervous system injury in vitro through the activation of Nrf2 signaling, displaying protective effects against mitochondrial dysfunction-derived OS (Yang et al., 2017).

Anti-inflammatory Activity

PTER has been recognized as an anti-inflammatory agent (Remsberg et al., 2008; Poulose et al., 2015; Kosuru et al., 2016) able to protect neurons against neuroinflammation due to the inhibition of ROS production (Shin et al., 2010). It acts on NF-kB and suppresses the action of various proinflammatory cytokines: TNF-α, IL-1β, IL-6 and IL-18 (Cichocki et al., 2008; Paul et al., 2009; Hou et al., 2014; El-Sayed et al., 2015) (Figure 3). PTER inhibits amyloid-β-induced neuroinflammation in microglia by inactivating the NLRP3/caspase-1 inflammasome pathway and reduces the secretion levels of IL-6, IL-1β and TNF-α, thereby attenuating the neuroinflammatory response, which would indicate that it could be a useful therapeutic strategy in neurodegenerative diseases (Li Q. et al., 2018; Seo et al., 2018).

Ability to Restore Intracellular Calcium

PTER is able to increase the capacity of intracellular calcium restoration by reducing recovery time after cell depolarization (Joseph et al., 2008). It protects against excitotoxicity, an aspect that would be interesting since it has been observed that the increase in intracellular ROS levels is related to damage in the cell membrane, impaired calcium homeostasis (Thibault et al., 2007; Joseph et al., 2011) and increased excitotoxicity (Rzheshevsky, 2014) (Figure 3). In the Sprague-Dawley rat model, PTER improves cholinergic transmission due to the decrease in the activity of acetylcholinesterase and increases the action of ATPases (Na⁺, K⁺, Ca²⁺, and Mg²⁺), which is indicative of the maintenance of the cell membrane potential (Naik et al., 2017).

Cognitive Function

After determining if PTER was effective in reversing the effects of aging in old Fischer rats, it was concluded that memory functioning was related to PTER levels in the hippocampus and that a diet supplemented with this antioxidant is effective in reversing deficits in cognitive behavior (Joseph et al., 2008). PTER attenuated lipopolysaccharide (LPS) induced learning and memory impairment, which is associated with an inhibition of the activation of microglia and therefore a protective effect against neuronal damage (Hou et al., 2014) (Figure 3). It reduces memory loss in the intracerebroventricular administered streptozotocin-induced memory decline in Sprague–Dawley rats (Naik et al., 2017) and mediates neuroprotection against oxidative toxicity via the estrogen receptor signaling pathway in human neuronal SH-SY5Y cells (Song et al., 2015).

In AD, supplementation with PTER reduces the phosphorylation of pTau (Porquet et al., 2013). The derivatives of PTER showed antioxidant and inhibitory activity against the aggregation of β-amyloid plaques, as well as cholinesterase inhibition, which would be useful in the treatment of patients with AD (Li Y. et al., 2016) and vascular dementia (Lange and Li, 2018).

PTER is a modulator of cognition and the OS due to the increased expression of peroxisome proliferator activator receptor alpha (PPAR-α) (Chang et al., 2012) (Figure 3). After comparing the effectiveness of dietary supplementation with RES and PTER in the improvement of functional deficits characteristic of AD in the SAMP8 mouse model (a model of accelerated aging that is increasingly being validated as a model of sporadic and age-related AD), it was concluded that PTER and not RES, is able to modulate the markers of cellular stress and inflammation, causing an upregulation of PPAR-α (Chang et al., 2012) and a suppression of the activation of NF-kB (Inoue et al., 2003), which is a conservative factor against the loss of cognitive function (Jeong et al., 2012; Hou et al., 2014) (Figure 3).

Due to the activation of metabolic pathways related to OS protection, inflammation, regulation of excitotoxicity and preservation of neuronal functions, PTER is a protective factor against neurodegenerative diseases (Poulose et al., 2015).

Conclusion

OS is involved in neuroinflammation, development and progression of ALS. The complex interaction between all the factors does not allow definitive determination if OS is a primary cause or if it is a secondary effect to the propagation of damage in the nervous cells. However, a clear relationship has been established between OS, mitochondrial dysfunction and neuroinflammation, aspects that promote a “vicious cycle” that causes a decrease in the capacity of ATP biosynthesis and an increase in ROS levels.

Currently, there is no cure for ALS but the use of different antioxidant substances has been proposed as a possible therapeutic strategy, the purpose of which is to increase the body’s antioxidant defenses and maintain the redox balance. However, there are cases in which the use of these antioxidants has disadvantages or requires a higher number of studies since few results are available or these are contradictory, inconclusive or scarcely significant at the statistical level. Taking into account the pathogenic mechanisms of ALS, the new therapeutic strategies have as the main goal to activate the metabolic pathways related to the mitochondria, production of energy and increase the antioxidant defense levels.

NAD⁺ acts on energy metabolism, mitochondrial function and is key in brain metabolism, aspects involved in the pathogenesis of ALS. Restoration of NAD⁺ levels by administrating the precursor NR provides greater mitochondrial resistance against impairment of redox balance and, therefore, could play a key role in those diseases that are associated with mitochondrial dysfunction and OS.

PTER has great biological potential due to its ability to activate metabolic pathways related to protection against OS, mitochondrial dysfunction, inflammation, intracellular calcium restoration and cognitive function, thus resulting in a neuroprotective function against the pathogenic mechanisms of ALS.

In a randomized, double-blind, placebo-controlled study in humans, it was determined that repeated doses of a combination therapy with NR and PTER increased NAD⁺ levels safely and effectively (Dellinger et al., 2017). Treatment with NR and PTER is effective and safe and therefore it could be a promising therapeutic strategy in ALS, due to its action on the pathogenesis of this disease.

References

• 1

  AbeK.AokiM.TsujiS.ItoyamaY.SobueG.TogoM.et al (2017). Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled trial.Lancet Neurol.16505–512. 10.1016/S1474-4422(17)30115-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 2

  AbeK.ItoyamaY.SobueG.TsujiS.AokiM.DoyuM.et al (2014). Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in Amyotrophic lateral sclerosis patients.Amyotroph. Lateral Scler. Frontotemporal. Degener.15610–617. 10.3109/21678421.2014.959024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 3

  AcharyaJ. D.GhaskadbiS. S. (2013). Protective effect of pterostilbene against free radical mediated oxidative damage.BMC Complement. Altern. Med.13:238. 10.1186/1472-6882-13-238

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 4

  AgarJ.DurhamH. (2003). Relevance of oxidative injury in the pathogenesis of motor neuron diseases.Amyotroph. Lateral Scler. Other Motor Neuron Disord.4232–242. 10.1080/14660820310011278

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 5

  AherneS. A.O’BrienN. M. (2002). Dietary flavonols: chemistry, food content, and metabolism.Nutrition1875–81.

  • Pubmed Abstract
  • Google Scholar

• 6

  AhmadiM.AgahE.NafissiS.JaafariM. R.HarirchianM. H.SarrafP.et al (2018). Safety and efficacy of nanocurcumin as add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a pilot randomized clinical trial.Neurotherapeutics15430–438. 10.1007/s13311-018-0606-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 7

  AhtoniemiT.JaronenM.Keksa-GoldsteinV.GoldsteinsG.KoistiahoJ. (2008). Mutant SOD1 from spinal cord of G93A rats is destabilized and binds to inner mitochondrial membrane.Neurobiol. Dis.32479–485. 10.1016/j.nbd.2008.08.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 8

  AirhartS. E.ShiremanL. M.RislerL. J.AndersonG. D.Nagana-GowdaG. A.RafteryD.et al (2017). An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers.PLoS One12:e0186459. 10.1371/journal.pone.0186459

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 9

  AkinwumiB. C.BorduK. A. M.AndersonH. D. (2018). Biological activities of stilbenoids.Int. J. Mol. Sci.19:E792. 10.3390/ijms19030792

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 10

  AlbarracínS. L.StabB.CasasZ.SutachanJ. J.SamudioI.GonzálezJ.et al (2012). Effects of natural antioxidants in neurodegenerative diseases.Nutr. Neurosci.151–9. 10.1179/1476830511Y.0000000028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 11

  AlbassamA. A.FryeR. F. (2019). Effect os pterostilbene on in vitro drug metabolizing enzyme activity.Saudi Pharm. J.27406–412. 10.1016/j.jsps.2019.01.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 12

  Al-ChalabiA.HardimanO. (2013). The epidemiology of ALS: a conspiracy of genes, environment and time.Nat. Rev. Neurol.9617–628. 10.1038/nrneurol.2013.203

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 13

  Al-ChalabiA.KwakS.MehlerM.RouleauG.SiddiqueT.StrongM.et al (2013). Genetic and epigenetic studies of amyotrophic lateral sclerosis.Amyotroph. Lateral Scler. Frontotemporal. Degener.1444–52. 10.3109/21678421.2013.778571

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 14

  Al-GuboryK. H.GarrelC.FaureP.SuginoN. (2012). Roles of antioxidant enzymes in corpus luteum rescue from reactive oxygen species-induced oxidative stress.Reprod. Biomed.25551–560. 10.1016/j.rbmo.2012.08.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 15

  AllenC. L.BayraktunanU. (2009). Oxidative stress and its role in the pathogenesis of ischaemic stroke.Int. J. Stroke4461–470. 10.1111/j.1747-4949.2009.00387.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 16

  AlquilanoK.BaldelliS.PaglieliB.CirioloM. R. (2013). Extranuclear localization of SIRT1 and PGC-1α: an insight into possible roles in diseases associated with mitochondrial dysfunction.Curr. Mol. Med.13140–154.

  • Pubmed Abstract
  • Google Scholar

• 17

  AmanY.QiuY.TaoJ.FangE. F. (2018). Therapeutic potential of boosting NAD+ in aging and age-related diseases.Transl. Med. Aging230–37. 10.1016/j.tma.2018.08.003

  • CrossRef
  • Google Scholar

• 18

  AndersenP. M. (2006). Amyotrophic lateral sclerosis associated with mutations in the CuZn superoxide dismutase gene.Curr. Neurol. Neurosci. Rep.637–46.

  • Pubmed Abstract
  • Google Scholar

• 19

  AndersenP. M.Al-ChalabiA. (2011). Clinical genetics of amyotrophic lateral sclerosis: what do we really know?Nat. Rev. Neurol.7603–615. 10.1038/nrneurol.2011.150

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 20

  AngelovaP. R.AbramovA. Y. (2018). Role of mitochondrial ROS in the brain: from physiology to neurodegeneration.FEBS. Lett.592692–702. 10.1002/1873-3468.12964

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 21

  An-NaL.ShaL.Yu-JieZ.Xiang-RongX.Yu-MingC.Hua-BinL. (2014). Resources and biological activities of natural polyphenols.Nutrients66020–6047. 10.3390/nu6126020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 22

  ArakiT.SasakiY.MilbrandtT. (2004). Increased nuclear NAD biosynthesis and SIRT1 activation prevent axonal degeneration.Science3051010–1013. 10.1126/science.1098014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 23

  ArunS.LiuL.DonmezG. (2016). Mitochondrial biology and neurological diseases.Curr. Neuropharmacol.14143–154.

  • Google Scholar

• 24

  AscherioA.WeisskopfM. G.O’reillyE. J.JacobsE. J.McCulloughM. L.CalleE. E.et al (2005). Vitamin E intake and risk of amyotrophic lateral sclerosis.Ann. Neurol.57104–110. 10.1002/ana.20316

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 25

  AtashiF.ModarressiA.PepperM. S. (2015). The role of reactive oxygen species in mesenchymal stem cell adipogenic and osteogenic di?erentiation: a review.Stem Cells Dev.241150–1163. 10.1089/scd.2014.0484

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 26

  AyalaA.MuñozM. F.ArgüellesS. (2014). Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-Hydroxy-2 nonenal.Oxid. Med. Cell. Longev.2014:360438. 10.1155/2014/360438

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 27

  BabuG. N.KumarA.ChandraR.PuriS. K.SinghR. L.KalitaJ.et al (2008). Oxidant-antioxidant imbalance in the erythrocytes of sporadic amyotrophic lateral sclerosis patients correlates with the progression of disease.Neurochem. Int.521284–1289. 10.1016/j.neuint.2008.01.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 28

  BaillyC. (2019). Potential use of edaravone to reduce specific side effects of chemo-, radio- and immuno-therapy of cancers.Int. Immunopharmacol.77:105967. 10.1016/j.intimp.2019.105967

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 29

  BalabanR. S.NemotoS.FinkelT. (2005). Mitochondria, oxidants and aging.Cell120483–495. 10.1016/j.cell.2005.02.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 30

  BannoM.MizunoT.KatoH.ZhangG.KawanokuchiJ.WangJ.et al (2005). The radical scavenger edaravone prevents oxidative neurotoxicity induced by peroxynitrite and activated microglia.Neuropharmacology48283–290. 10.1016/j.neuropharm.2004.10.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 31

  BaoA. M.SwaabD. F. (2018). The art of matching brain tissue from patients and controls for postmortem research.Handb. Clin. Neurol.150197–217. 10.1016/B978-0-444-63639-3.00015-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 32

  BarberS. C.ShawP. J. (2010). Oxidative stress in ALS: key role in motor neuron injury and therpaeutic target.Free Radic. Biol. Med.48629–641. 10.1016/j.freeradbiomed.2009.11.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33

  BäumerD.TalbotK.TurnerM. R. (2014). Advances in motor neuron disease.J. R. Soc. Med.10714–21. 10.1177/0141076813511451

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 34

  BayerH.LangK.BuckE.HigelinJ.BarteczkoL.PasquarelliN.et al (2017). ALS-causing mutations differentially affect PGC-1α expression and function in the brain vs. peripheral tissues.Neurobiol. Dis.97(Pt A), 36–45. 10.1016/j.nbd.2016.11.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 35

  BealM. F. (2002). Oxidatively modified protein in aging and disease.Free Radic. Biol. Med.32797–803.

  • Google Scholar

• 36

  BealM. F.LangA. E.LudolphA. (2005). Neurodegenerative diseases: neurobiology, pathogenesis, and therapeutics.J. Neurol. Neurosurg. Psychiatry77:284. 10.1136/jnnp.2005.072710

  • CrossRef
  • Google Scholar

• 37

  BedlackR. S.JoyceN.CarterG. T.PagononiS.KaramC. (2015). Complementary and alternative therapies in ALS.Neurol. Clin.33909–936. 10.1016/j.ncl.2015.07.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 38

  BelenkyP.RacetteF. G.BoganK. L.McClureJ. M.SmithJ. S.BrennerC. (2007). Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+.Cell129473–484. 10.1016/j.cell.2007.03.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 39

  BendottiC.TortaroloM.SuchakS. K.CalvaresiN.CarvelliL.BastoneA.et al (2001). Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels.J. Neurochem.79737–746.

  • Pubmed Abstract
  • Google Scholar

• 40

  BennettG. J.DoyleT.SalveminiD. (2014). Mitotoxicity in distal symmetrical sensory peripheral neuropathies.Nat. Rev. Neurol.10326–336. 10.1038/nrneurol.2014.77

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41

  BergerF.Ramírez-HernándezM. H.ZieglerM. (2004). The new life of a centenarian: signalling functions of NAD(P).Trends Biochem. Sci.29111–118. 10.1016/j.tibs.2004.01.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 42

  BhakkiyalakshmiE.DineshkumarK.KarthikS.SireeshD.HopperW.PaulmuruganR.et al (2016). Pterostilbene-mediated Nrf2 activation: mechanistic insights on Keap1: Nrf2 interface.Bioorg. Med. Chem.243378–3386. 10.1016/j.bmc.2016.05.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 43

  BhatA. H.DarK. B.AneesS.ZargarM. A.MasoodA.SofiM. A.et al (2015). Oxidative stress, mitocondrial dysfunction and neurodegenerative diseases; a mechanistic insight.Biomed. Pharmacother.74101–110. 10.1016/j.biopha.2015.07.025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 44

  BhatiaN. K.SrivastavaA.KatyalN.JainN.KhanM. A.KunduB.et al (2015). Curcumin binds to the pre-fibrillar aggregates of Cu/Zn superoxide dismutase (SOD1) and alters its amyloidogenic pathway resulting in reduced cytotoxicity.Biochim. Biophys. Acta1854426–436. 10.1016/j.bbapap.2015.01.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 45

  BhattacharyaR.HarveyR. A.AbrahamK.RosenJ.MehtaP. (2019). Amyotrophic lateral sclerosis among patients with a Medicare Advantage prescription drug plan; prevalence, survival and patient characteristics.Amyotroph. Lateral Scler. Frontotemporal. Degener.201–9. 10.1080/21678421.2019.1582674

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 46

  BhullarK. S.VasanthaH. P. (2013). Polyphenols: multipotent therapeutic agents in neurodegenerative diseases.Oxid. Med. Cell. Longev.2013:891748. 10.1155/2013/891748

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 47

  BieganowskiP.BrennerC. (2004). Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans.Cell117495–502.

  • Pubmed Abstract
  • Google Scholar

• 48

  BlascoH.GarconG.PatinF.Veyrat-DurebexC.BoyerJ.DevosD.et al (2017). Panel of oxidative stress and inflammatory biomarkers in ALS: a pilot study.Can. J. Neurol. Sci.4490–95. 10.1017/cjn.2016.284

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 49

  BlokhuisA. M.GroenE. J. N.KoppersM.Van Den BergL.-H.PasterkampR. J. (2013). Protein aggregation in amyotrophic lateral sclerosis.Acta Neuropathol.125777–794. 10.1007/s00401-013-1125-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 50

  BoganK. L.BrennerC. (2008). Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition.Annu. Rev. Nutr.28115–130. 10.1146/annurev.nutr.28.061807.155443

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 51

  BondL.BernhardtK.MadriaP.SorrentinoK.ScelsiH.MitchellC. S. (2018). A metadata analysis of oxidative stress etiology in preclinical amyotrophic lateral sclerosis: benefits of antioxidant therapy.Front. Neurosci.12:10. 10.3389/fnins.2018.00010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 52

  BonkowskiM. S.SinclairD. A. (2016). Slowing ageing by design: the rise of NAD+ and sirtuin-activation compounds.Nat. Rev. Mol. Cell Biol.17679–690. 10.1038/nrm.2016.93

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 53

  Bonnefont-RousselotD. (2016). Resveratrol and cardiovascular diseases.Nutrients8:E250. 10.3390/nu8050250

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 54

  BozzoF.MirraA.CarrìM. T. (2016). Oxidative stress and mitochondrial damage in the pathogenesis of ALS: new perspectives.Neurosci. Lett.6363–8. 10.1016/j.neulet.2016.04.065

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 55

  BraidyN.GuilleminG.GrantR. (2008). Promotion of cellular NAD(+) anabolism: therapeutic potential for oxidative stress in ageing and Alzheimer’s disease.Neurotox. Res.13173–184.

  • Google Scholar

• 56

  BriegerK.SchiavoneS.MillerF. J.KrauseK. H. (2012). Reactive oxygen species: from health to disease.Swiss Med. Wkly.142:w13659. 10.4414/smw.2012.13659

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 57

  BrookesP. S.YoonY.RobothamJ. L.AndersM. W.SheuS. S. (2004). Calcium, ATP and ROS. A mitochondrial love-hate triangle.Am. J. Physiol. Cell Physiol.287C817–C833. 10.1152/ajpcell.00139.2004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 58

  BrownK. D.MaqsoodS.HuangJ. Y.PanY.HarkcomW.LiW.et al (2014). Activation of SIRT3 by the NAD+ precursor nicotinamide riboside protects from noise-induced hearing loss.Cell Metab.201059–1068. 10.1016/j.cmet.2014.11.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 59

  BrownR. H.Al-ChalabiA. (2017). Amyotrophic lateral sclerosis.N. Engl. J. Med.377162–172. 10.1056/NEJMra1603471

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 60

  BrujinL. I.MillerT. M.ClevelandD. W. (2004). Unraveling the mechanism involved in motor neuron degeneration in ALS.Annu. Rev. Neurosci.27723–749. 10.1146/annurev.neuro.27.070203.144244

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 61

  BuckE.BayerH.LindenbergK. S.HanselmannJ.PasquarelliN.LudolphA. C.et al (2017). Comparison of sirtuin 3 levels in ALS and Huntington’s disease-differential effects in human tissue samples vs. transgenic mouse models.Front. Mol. Neurosci.10:156. 10.3389/fnmol.2017.00156

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 62

  BulottaS.CelanoM.LeporeS. M.MontalciniT.PujiaA.RussoD. (2014). Beneficial effects of olive oil phenolic components oleuropein and hydroxytirosol: focus on protection against cardiovascular and metabolic diseases.J. Transl. Med.12:219. 10.1186/s12967-014-0219-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 63

  BurgosE. S.VetticattM. J.SchrammV. L. (2013). Recycling nicotinamide. The transition-state structure of human nicotinamide phosphoribosyltransferase.J. Am. Chem. Soc.1353485–3493. 10.1021/ja310180c

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 64

  ButterfieldD. A.CastegnaA.DrakeJ.ScapagniniG.CalabreseV. (2002). Vitamin E and neurodegenerative disorders associated with oxidative stress.Nutr. Neurosci.5229–239. 10.1080/10284150290028954

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 65

  CamandolaS.MattsonM. P. (2011). Aberrant subcellular neuronal calcium regulation in aging and Alzheimer’s disease.Biochim. Biophys. Acta.1813965–973. 10.1016/j.bbamcr.2010.10.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 66

  CantóC.HoutkooperR. H.PirinenE.YounD. Y.OosterveerM. H.ChenY.et al (2012). The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high fat diet-induced obesity.Cell Metab.15838–847. 10.1016/j.cmet.2012.04.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 67

  CantóC.MenziesK. J.AuwersJ. (2015). NAD(+) metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus.Cell Metab.2231–53. 10.1016/j.cmet.2015.05.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 68

  CaoG.SoficE.PriorR. L. (1997). Antioxidant and prooxidant behavior of flavonoids: structure-activity relationships.Free Radic. Biol. Med.22749–760.

  • Pubmed Abstract
  • Google Scholar

• 69

  CareyA. N.FisherD. R.RimandoA. M.GomesS. M.BielinskiD. F.Shukitt-HaleB. (2013). Stilbenes and anthocyanins reduce stress signaling in BV-2 mouse microglia.J. Agric. Food. Chem.615979–5986. 10.1021/jf400342g

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 70

  CarrìM. T.ValleC.BozzoF.CozzolinoM. (2015). Oxidative stress and mitochondrial damage: importance in non-SOD1 ALS.Front. Cell. Neurosci.9:41. 10.3389/fncel.2015.00041

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 71

  CarvalhoC.MoreiraP. I. (2018). Oxidative stress: a major player in cerebrovascular alterations associated to neurodegenerative events.Front. Physiol.9:806. 10.3389/fphys.2018.00806

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 72

  CarvalhoJ. C. T.FernandesC. P.DalepraneJ. B.AlvesM. S.StienD.DhammikaN. P. (2018). Role of natural antioxidants from functional foods in neurodegenerative and metabolic disorders.Oxid. Med. Cell. Longev.2018:1459753. 10.1155/2018/1459753

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 73

  CastellaniR. J.LeeH. G.ZhuX.PerryG.SmithM. A. (2008). Alzheimer diseases pathology as a host response.J. Neurpathol. Exp. Neurol.67523–531. 10.1097/NEN.0b013e318177eaf4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 74

  ChandrasekaranA.IdelchikM. D. P. S.MelendezJ. A. (2017). Redox control of senescence and age-related disease.Redox. Biol.1191–102. 10.1016/j.redox.2016.11.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 75

  ChangH. C.GuarenteL. (2013). SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging.Cell1531448–1460. 10.1016/j.cell.2013.05.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 76

  ChangJ.RimandoA.PallasM.CaminsA.PorquetD.ReevesJ.et al (2012). Low-dose perostilbene, but not resveratrol, is a potent neuromodulator in aging and Alzheimer’s disease.Neurobiol. Aging332062–2071. 10.1016/j.neurobiolaging.2011.08.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 77

  ChangY.KongQ.ShanX.TianG.IlieveaH.ClevelandD. W.et al (2008). Messenger RNA oxidation occurs early in disease pathogenesis and promotes motor neuron degeneration in ALS.PLoS One3:e2849. 10.1371/journal.pone.0002849

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 78

  ChenQ.WangQ.ZhuJ.XiaoQ.ZhangL. (2018). Reactive oxygen species: key regulators in vascular health and diseases.Br. J. Pharmacol.1751279–1292. 10.1111/bph.13828

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 79

  ChenS.SayanaP.ZhangX.LeW. (2013). Genetics of amyotrophic lateral sclerosis: an update.Mol. Neurodegener.8:28. 10.1186/1750-1326-8-28

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80

  ChenY.ZhangJ.LinY.LeiQ.GuanK. L.ZhaoS.et al (2011). Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROS.EMBO Rep.12534–541. 10.1038/embor.2011.65

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 81

  ChengY.DiS.FanC.CaiL.GaoC.JiangP.et al (2016). SIRT1 activation by pterostilbene attenuates the skeletal muscle oxidative stress injury and mitochondrial dysfunction induced by ischemia reperfusion injury.Apoptosis21905–916. 10.1007/s10495-016-1258-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 82

  ChiY.SauveA. (2013). Nicotinamide riboside, a trace nutrient in foods, is a Vitamina B3 with effects on energy metabolism and neuroprotection.Curr. Opin. Clin. Nutr. Metab. Care16657–661. 10.1097/MCO.0b013e32836510c0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 83

  ChicoL.LencoE. C.BisordiC.Lo GerfoA.PetrozziL.PetrucciA.et al (2018). Amyotrophic lateral sclerosis and oxidative stress: a double-blind therapeutic trial after curcumin supplementation.CNS Neurol. Disord. Drug Targets17767–779. 10.2174/1871527317666180720162029

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 84

  ChiòA.LogroscinoG.TraynorB. J.CollinsJ.SimeoneJ. C.GoldsteinL. A.et al (2013). Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature.Neuroepidemiology41118–130. 10.1159/000351153

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 85

  ChiouY. S.TsaiM. L.NagabhusanamK.WangY. J.WuC. H.HoC. T.et al (2011). Pterostilbene is more potent that resveratrol in preventing azoxymethane (AOM)-induced colon tumorigenesis via activation of the NF-E2-related factor 2 (Nrfe2)-mediated antioxidant signaling pathway.J. Agric. Food Chem.592725–2733. 10.1021/jf2000103

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 86

  ChooQ. Y.Ming-YeoS. C.HoP. C.TanakaY.LinH. S. (2014). Pterostilbene surpassed resveratrol for anti-inflammatory application: potency consideration and pharmacokinetics perspective.J. Funct. Food11352–362. 10.1016/j.jff.2014.10.018

  • CrossRef
  • Google Scholar

• 87

  ChungS.YaoH.CaitoS.HwangJ. W.ArunachalamG.RahmanI. (2010). Regulation of SIRT1 in cellular functions: role of polyphenols.Arch. Biochem. Biophys.50179–90. 10.1016/j.abb.2010.05.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 88

  CichockiM.PaluszczakJ.SzaeferH.PiechowiakA.RimandoA. M.Baer-DubowskaW. (2008). Pterostilbene is equally as potent as resveratrol in inhibiting 12-O-tetradecanoylphorbol-13-acetate activated NFkappaB, AP-1. COX-2 and iNOS in mouse epidermis.Mol. Nutr. Food Res.52(Suppl. 1), S62–S70. 10.1002/mnfr.200700466

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 89

  CoanG.MitchellC. S. (2015). An assessment of possible neuropathology and clinical relationships in 46 sporadic amyotrophic lateral sclerosis patient autopsies.Neurodegener. Dis.15301–312. 10.1159/000433581

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 90

  CohenT. J.HwangA. W.RestrepoC. X.YuanJ. Q.TrojanowskiJ. Q.LeeV. M. (2015). An acetylation switch controls TDP-43 function and aggregation propensity.Nat. Commun.6:5845. 10.1038/ncomms6845

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 91

  CohenT. J.HwangA. W.UngerT.TrojanowskiJ. Q.LeeV. M. (2012). Redox signaling directly regulates TDP-43 via cysteine oxidation and disulphide cross-linking.EMBO J.311241–1252. 10.1038/emboj.2011.471

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 92

  ColbourneJ.BakerN.WangP.LiuL.TuckerC.RoebothanB. (2013). Adequacy of niacin, folate, and vitamin B12 intakes from foods among Newfoundland and Labrador adults.Can. J. Diet. Pract. Res.7463–68. 10.3148/74.2.2013.63

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 93

  ColemanM. (2005). Axon degeneration mechanisms: commonality amid diversity.Nat. Rev. Neurosci.6889–898. 10.1038/nrn1788

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 94

  ConfortiL.FangG.BeirowskiB.WangM. S.SorciL.AsressS.et al (2006). NAD(+) and axon degeneration revisited: Nmnat 1 cannot substitute for Wld(S) to delay Wallerian degeneration.Cell Death Differ.14116–127. 10.1038/sj.cdd.4401944

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 95

  CookeM. S.EvansM. D.HerbertK. E.LunecJ. (2000). Urinary 8-oxo-2’-deoxyguanosine—source, significance and supplements.Free Radic. Res.32381–397.

  • Pubmed Abstract
  • Google Scholar

• 96

  CookeM. S.LunecJ.EvansM. D. (2002). Progress in the analysis of urine oxidative DNA damage.Free Radic. Biol. Med.331601–1614.

  • Pubmed Abstract
  • Google Scholar

• 97

  CoppedèF.MiglioreL. (2015). DNA damage in neurodegenerative diseases.Mutat. Res.77684–97. 10.1016/j.mrfmmm.2014.11.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 98

  CordeiroR. M. (2014). Reactive oxygen species at phospholipid bilayers: distribution, mobility and permation.Biochim. Biophys. Acta.1838438–444. 10.1016/j.bbamem.2013.09.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 99

  CorreiaS. C.CarvalhoC.CardosoS.SantosR. X.SantosM. S.OliveiraC. R.et al (2010). Mitochondrial preconditioning: a potential neuroprotective strategy.Front. Aging Neurosci.2:138. 10.3389/fnagi.2010.00138

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 100

  CorreiaS. C.MoreiraP. I. (2010). Hypoxia-inducible factor 1: a new hope to counteract neurodegeneration?J. Neurochem.1121–12. 10.1111/j.1471-4159.2009.06443.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 101

  CoryH.PassarelliS.SzetoJ.TamezM.MatteiJ. (2018). The role of polyphenols in human health and food systems: a mini-review.Front. Nutr.5:87. 10.3389/fnut.2018.00087

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 102

  CovaE.BongioanniP.CeredaC.MetelliM. R.SalvaneschiL.BernuzziS.et al (2010). Time course of oxidant markers and antioxidant defenses in subgroups of amyotrophic lateral sclerosis patients.Neurochem. Int.56687–693. 10.1016/j.neuint.2010.02.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 103

  CovingtonJ. D.BajpeyiS. (2016). The sirtuins: markers of metabolic health.Mol. Nutr. Food Res.6079–91. 10.1002/mnfr.201500340

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 104

  CoyleJ. T.PuttfarckenP. (1993). Oxidative stress, glutamate and neurodegenerative disorders.Science262689–695.

  • Google Scholar

• 105

  CozzolinoM.CarrìM. T. (2012). Mitochondrial dysfunction in ALS.Prog. Neurobiol.9754–66. 10.1016/j.pneurobio.2011.06.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 106

  CrozierA.JaganathI. B.CliffordM. N. (2009). Dietary phenolics: chemistry, bioavailability and effects on health.Nat. Prod. Rep.261001–1043. 10.1039/b802662a

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 107

  CzpaskiG. A.CzubowiczK.StrosznajderR. P. (2012). Evaluation of the antioxidative properties of lypoxygenase inhibitors.Pharmacol. Rep.641179–1188.

  • Google Scholar

• 108

  DahlqvistJ. R.OestergaardS. T.PoulsenN. S.KankK. L.ThomsenC.VissingJ. (2019). Muscle contractility in spinobulbar muscular atrophy.Sci. Rep.9:4680. 10.1038/s41598-019-41240-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 109

  D’AmicoE.Factor-LitvakP.SantellaR. M.MitsumotoH. (2013). Clinical perspective of oxidative stress in sporadic ALS.Free Radic. Biol. Med.65509–527. 10.1016/j.freeradbiomed.2013.06.029

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 110

  DardiotisE.PanayiotouE.FeldmanM. L.HadjisavvasA.MalasS.VontaI.et al (2013). Intraperitoneal melatonin is not neuroprotective in the g93asod1 transgenic mouse model of familial als and may exacerbate neurodegeneration.Neurosci. Lett.548170–175. 10.1016/j.neulet.2013.05.058

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 111

  DavidsonM. H. (2008). Niacin use and cutaneous flushing: mechanisms and strategies for prevention.Am. J. Cardiol.10114B–19B. 10.1016/j.amjcard.2008.02.028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 112

  De GaraL.FoyerC. H. (2017). Ying and Yang interplay between reactive oxygen and reactive nitrogen species controls cells functions.Plant Cell Environ.40459–461. 10.1111/pce.12936

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 113

  De SilvaT. M.MillerA. A. (2016). Cerebral small vessel diseases: targeting oxidative stress as a novel therapeutic strategy?Front. Pharmacol.17:61. 10.3389/fphar.2016.00061

  • CrossRef
  • Google Scholar

• 114

  DellingerR. W.Roel-SantosS.MorrisM.EvansM.AlminanaD.GuarenteL.et al (2017). Repeat dose NRPT (nicotinamide riboside and pterostilbene) increases NAD+ levels in humans safely and sustainably: a randomized, doublé-blind, placebo-controlled study.NPJ Aging Mech. Dis.3:17. 10.1038/s41514-017-0016-9

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 115

  DengH. X.ShiY.FurukawaY.ZhaiH.FuR.LiuE.et al (2006). Conversion to the amyotrophic lateral sclerosis phenotype is associated with intermolecular linked insoluble aggregates of SOD1 in mitochondria.Proc. Natl. Acad. Sci. U.S.A.1037142–7147. 10.1073/pnas.0602046103

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 116

  DesnuelleC.DibM.GarrelC.FavierA. (2001). A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group.Amyotroph. Lateral Scler. Other Motor Neuron Disord.29–18.

  • Pubmed Abstract
  • Google Scholar

• 117

  Di MatteoV.EspositoE. (2003). Biochemical and therapeutic effects of antioxidants in the treatment of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis.Curr. Drug Targets CNS Neurol. Disord.295–107.

  • Pubmed Abstract
  • Google Scholar

• 118

  Di PietroL.BaranziniM.BerardinelliM. G.LattanziW.MonforteM.TascaG.et al (2017). Potential therapeutic targets for ALS: MIR206, MIR208b and MIR499 are modulated during disease progression in the skeletal muscle of patients.Sci. Rep.7:9538. 10.1038/s41598-017-10161-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 119

  DiasV.JunnE.MouradianM. (2013). The role of oxidative stress in Parkinson’s diseases.J. Parkinsons Dis.3461–491. 10.3233/JPD-130230

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 120

  DingG.FuM.QuinQ.LewisW.KimH. W.FukaiT.et al (2007). Cardiac peroxisome proliferator-activated receptor gamma is essential in protecting cardiomyocytes from oxidative damage.Cardiovasc. Res.76269–279. 10.1016/j.cardiores.2007.06.027

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 121

  DirnaglU.BeckerK.MeiselA. (2009). Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use.Lancet Neurol.8398–412. 10.1016/S1474-4422(09)70054-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 122

  DirnaglU.MeiselA. (2008). Endogenous neuroprotection: mitochondria as gateways to cerebral preconditioning?Neuropharmacology55334–344. 10.1016/j.neuropharm.2008.02.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 123

  DixonS. J.StockwellB. R. (2014). The role of iron and reactive oxygen species in cell death.Nat. Chem. Biol.109–17. 10.1038/nchembio.1416

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 124

  DizdarogluM.JarugaP. (2012). Mechanism of free radical-induced damage to DNA.Free Radic. Res.46382–419. 10.3109/10715762.2011.653969

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 125

  DolopikouC. F.KourtzidisI. A.MargaritelisN. V.VrabasI. S.KoidouI.KyparosA.et al (2019). Acute nicotinamide riboside supplementation improves redox homeostasis and exercise performance in old individuals: a double-blind cross-over study.Eur. J. Nutr.10.1007/s00394-019-01919-4[Epub ahead of print].

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 126

  DongH.XuL.WuL.WangX.DuanW.LiH.et al (2014). Curcumin abolishes mutant TDP-43 induced excitability in a motoneuron-like cellular model of ALS.Neuroscience272141–153. 10.1016/j.neuroscience.2014.04.032

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 127

  DorstJ.LudolphA. C.HuebersA. (2017). Disease-modifying and symptomatic treatment of amyotrophic lateral sclerosis.Ther. Adv. Neurol. Disord.11:1756285617734734. 10.1177/1756285617734734

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 128

  DuY.WuH. T.QuinX. Y.CaoC.LiuY.CaoZ. Z.et al (2018). Postmortem brain, cerebrospinal fluid, and blood neurotrophic factor levels in Alzheimer’s disease: a systematic review and meta-analysis.J. Mol. Neurosci.65289–300. 10.1007/s12031-018-1100-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 129

  DuanW.LiX.ShiJ.GuoY.LiZ.LiC. (2010). Mutant TAR DNA-binding protein-43 induces oxidative injury in motor neuron-like cell.Neuroscience1691621–1629. 10.1016/j.neuroscience.2010.06.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 130

  DuffyL. M.ChapmanA. L.ShawP. J.GriersonA. J. (2011). Review: the role of mitochondria in the pathogenesis of amyotrophic lateral sclerosis.Neuropathol. Appl. Neurobiol.37336–352. 10.1111/j.1365-2990.2011.01166.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 131

  DupuisL.PradatP. F.LudolphA. C.LoefflerJ. P. (2011). Energy metabolism in amyotrophic lateral sclerosis.Lancet Neurol.1075–82. 10.1016/S1474-4422(10)70224-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 132

  DvorakovaM.LandaP. (2017). Anti-inflammatory activity of natural stilbenoids: a review.Pharmacol. Res.124126–145. 10.1016/j.phrs.2017.08.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 133

  DyckG. J. B.RajP.ZierothS.DyckJ. R. B.EzekowitzJ. A. (2019). The effects of resveratrol in patients with cardiovascular disease and heart failure: a narrative review.Int. J. Mol. Sci.20:E904. 10.3390/ijms20040904

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 134

  EhrhartJ.SmithA. J.Kuzmin-NicholsN.ZesiewiczT. A.JahanI.ShytleR. D.et al (2015). Humoral factors in ALS patients during disease progression.J. Neuroinflammation12:127. 10.1186/s12974-015-0350-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 135

  El-SayedS. M.MansourA. M.NadyM. E. (2015). Protective effects of pterostilbene against actaminophen-induced hepatotoxicity in rats.J. Biochem. Mol. Toxicol.2935–42. 10.1002/jbt.21604

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 136

  EmeritJ.EdeasM.BricaireF. (2004). Neurodegenerative diseases and oxidative stress.Biomed. Pharmacother.5839–46.

  • Pubmed Abstract
  • Google Scholar

• 137

  EspositoE.CapassoM.di TomassoN.CoronaC.PellegriniF.UnciniA.et al (2007). Antioxidant strategies based on tomato- enriched food or pyruvate do not affect disease onset and survival in an animal model of amyotrophic lateral sclerosis.Brain Res.116890–96. 10.1016/j.brainres.2007.06.095

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 138

  EspositoE.RotilioD.Di MatteoV.Di GiulioC.CacchioM.AlgeriS. (2002). A review of specific dietary antioxidants and the effects on biochemical mechanisms related to neurodegenerative processes.Neurobiol. Aging23719–735.

  • Pubmed Abstract
  • Google Scholar

• 139

  EssaM. M.SubashS.BraidyN.AdawiS.LimC. K.ManivasagamT.et al (2013). Role of NAD+, oxidative and tryptophan metabolism in autism spectrum disorders.Int. J. Tryptophan Res.615–28. 10.4137/IJTR.S11355

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 140

  EstrelaJ. M.OrtegaA.MenaS.RodriguezM. L.AsensiM. (2013). Pterostilbene: biomedical applications.Crit. Rev. Clin. Lab. Sci.5065–78. 10.3109/10408363.2013.805182

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 141

  FalkowskiP. G.GodfreyL. V. (2008). Electrons, life an the evolution of Earth’s oxygen cycle.Philos. Trans. R. Soc. Lond. B Biol. Sci.3632705–2716. 10.1098/rstb.2008.0054

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 142

  FedericoA.CardaioliE.Da PozzoP.FormichiP.GallusG. N.RadiE. (2012). Mitochondria, oxidative stress and neurodegeneration.J. Neurol. Sci.322254–262. 10.1016/j.jns.2012.05.030

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 143

  FerranteK. L.ShefnerJ.ZhangH.BetenskyR.O’BrienM.YuH.et al (2005). Tolerance of high-dose (3,000 mg/day) coenzyme Q10 in ALS.Neurology561834–1836. 10.1212/01.wnl.0000187070.35365.d7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 144

  FerriA.CozzolinoM.CrosioC.NenciniM.CasciatiA.GrallaE. B.et al (2006). Familial ALS-superoxide dismutases associate with mitocondria and shift their redox potentials.Proc. Natl. Acad. Sci. U.S.A.10313860–13865. 10.1073/pnas.0605814103

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 145

  FialaM.MizwickiM. T.WeitzmanR.MagpantayL.NishimotoN. (2013). Tocilizumab infusión therapy normalizes inflammation in sporadic ALS patients.Am. J. Neurodegener. Dis.2129–139.

  • Google Scholar

• 146

  FiedorJ.SulikowskaA.OrzechowskaA.FiedorL.BurdaK. (2012). Antioxidant effects of carotenoids in a model pigment-protein complex.Acta Biochim. Pol.5961–64.

  • Pubmed Abstract
  • Google Scholar

• 147

  FischerR.MaierO. (2015). Interrelation of oxidative stress and inflammation in neurodegenerative disease: role of TNF.Oxid. Med. Cell. Longev.2015:610813. 10.1155/2015/610813

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 148

  FitzgeraldK. C.O’ReillyÉJ.FondellE.FalconeG. J.McCulloughM. L.ParkY.et al (2013). Intakes of vitamin C and carotenoids and risk of amyotrophic lateral sclerosis: pooled results from 5 cohort studies.Ann. Neurol.73236–245. 10.1002/ana.23820

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 149

  FlattT. (2012). A new definition of aging?Front. Genet.3:148. 10.3389/fgene.2012.00148

  • CrossRef
  • Google Scholar

• 150

  FletcherR. S.RatajczakJ.DoigC. L.OakeyL. A.CallinghamR.Da Silva-XavierG.et al (2017). Nicotinamide riboside kinases display redundancy in mediating nicotinamide mononucleotide and nicotinamide riboside metabolism in skeletal muscle cells.Mol. Metab.6819–832. 10.1016/j.molmet.2017.05.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 151

  FormellaI.SvahnA. J.RadfordR. A. W.DonE. K.ColeN. J.HoganA.et al (2018). Real-time visualization of oxidateive stress-mediated neurodegeneration of individual spinal motor neurons in vivo.Redox. Biol.19226–234. 10.1016/j.redox.2018.08.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 152

  FörstermannU.SessaW. C. (2012). Nitric oxide synthases: regulation and function.Eur. Heart. J.33829–837. 10.1093/eurheartj/ehr304

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 153

  FrederickD. W.LoroE.LiuL.DavilaA. J.ChellappaK.SilvermanI. M.et al (2016). Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle.Cell Metab.24269–282. 10.1016/j.cmet.2016.07.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 154

  FreemanL. R.KellerJ. N. (2012). Oxidative stress and cerebral endotelial cells: regulation of the blood-brain-barrier and antioxidant based interventions.Biochim. Biophys. Acta1822822–829. 10.1016/j.bbadis.2011.12.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 155

  FritzK. S.PetersenD. R. (2013). An overview of the chemistry and biology of reactive aldehydes.Free. Radic. Biol. Med.5985–91. 10.1016/j.freeradbiomed.2012.06.025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 156

  FuL.XuB. T.GanR. Y.ZhangY. A.XuR.XiaE. Q.et al (2011). Total phenolic contents and antioxidant capacities of herbal and tea infusions.Int. J. Mol. Sci.122112–2124. 10.3390/ijms12042112

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 157

  GalbusseraA.TremolizzoL.BrighinaL.TestaD.LovatiR.FerrareseC.et al (2006). Vitamin E intake and quality of life in amyotrophic lateral sclerosis patients: a follow-up case series study.Neurol. Sci.27190–193. 10.1007/s10072-006-0668-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 158

  GamezJ.Corbera-BellaltaM.NogalesG.RaguerN.García-ArumíE.Badia-CantoM.et al (2006). Mutational analysis of the Cu/Zn superoxide dismutase gen in a Catalan ALS population: should all sporadic ALS cases also be screened for SOD1?J. Neurol. Sci.24721–28. 10.1016/j.jns.2006.03.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 159

  GandhiS.AbramovA. Y. (2012). Mechanism of oxidative stress in neurodegeneration.Oxid. Med. Cell. Longev.2012:428010. 10.1155/2012/428010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 160

  GanesanK.XuB. (2017). Polyphenol-rich lentils ant their health promoting effects.Int. J. Mol. Sci.18:E2390. 10.3390/ijms18112390

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 161

  GanieS. A.DarT. A.BhatA. H.DarK. B.AneesS.ZargarM. A.et al (2016). Melatonin: a potential anti-oxidant therapeutic agent for mitochondrial dysfunctions and related disorders.Rejuvenation Res.1921–40. 10.1089/rej.2015.1704

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 162

  GhasemiF.BagheriH.BarretoG. E.ReadM. I.SahebkarA. (2019). Effects of curcumin on microgial cells.Neurotox. Res.3612–26. 10.1007/s12640-019-00030-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 163

  GhasemiM. (2016). Amyotrophic lateral sclerosis mimic syndromes.Iran. J. Neurol.1585–91.

  • Pubmed Abstract
  • Google Scholar

• 164

  GoleniaA.LeskiewiczM.RegulskaM.BudziszewskaB.SzczesnyE.JagiellaJ.et al (2014). Catalase activity in blood fractions of patients with sporadic ALS.Pharmacol. Rep.66704–707. 10.1016/j.pharep.2014.02.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 165

  GomesA. P.PriceN. L.LingA. J.MoslehiJ. J.MontogomeryM. K.RajmanL.et al (2013). Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging.Cell1551624–1638. 10.1016/j.cell.2013.11.037

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 166

  Gomez-ZoritaS.TréguerK.MercaderJ.CarpénéC. (2013). Resveratrol directly affects in vitro lipolysis and glucose transport in human fat cells.J. Physiol. Biochem.69585–593. 10.1007/s13105-012-0229-220

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 167

  GongB.PanY.VempatiP.ZhaoW.KnableL.HoL.et al (2013). Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-γ coactivator 1α regulated ß-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models.Neurobiol. Aging341581–1588. 10.1016/j.neurobiolaging.2012.12.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 168

  GonzálezD.ContrerasO.RebolledoD. L.EspinozaJ. P.Van ZundertB.BrandanE. (2017). ALS skeletal muscle shows enhanced TGF-ß signaling, fibrosis and induction of fibro/adipogenic progenitor markers.PLoS One12:e0177649. 10.1371/journal.pone.0177649

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 169

  GoodyM. F.HenryC. A. (2018). A need for NAD+ in muscle development, homeostasis, and aging.Skelet. Muscle8:9. 10.1186/s13395-018-0154-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 170

  GordonP. H. (2013). Amyotrophic lateral sclerosis: an update for 2013 clinical features, pathophysiology, management and therapeutic trials.Aging Dis.4295–310. 10.14336/AD.2013.0400295

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 171

  GordonP. H.MehalJ. M.HolamnR. C.RowlandL. P.RowlandA. S.CheekJ. E. (2013). Incidence of amyotrophic lateral sclerosis among American Indians and Alaska natives.JAMA Neurol.70476–480. 10.1001/jamaneurol.2013.929

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 172

  GowlandA.Opie-MartinS.ScottK. M.JonesA. R.MehtaP. R.BattsC. J.et al (2019). Predicting the future of ALS: the impact of demographic change and potential new treatments on the prevalence of ALS in the United Kingdom, 2020-2116.Amyotroph. Lateral Scler. Frontotemporal. Degener.20264–274. 10.1080/21678421.2019.1587629

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 173

  GrafM.EckerD.HorowskiR.KramerB.RiedererP.GerlachM.et al (2005). High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study.J. Neural Transm.112649–660. 10.1007/s00702-004-0220-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 174

  GreenK. N.SteffanJ. S.Martínez-CoriaH.SunX.SchreiberS. S.ThompsonL. M.et al (2008). Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via mechanism involving sirtuin inhibiton and selective reduction of Thr231-phosphotau.J. Neurosci.2811500–11510. 10.1523/JNEUROSCI.3203-08.2008

  • CrossRef
  • Google Scholar

• 175

  GrochowskiC.LitakJ.KamieniakP.MaciejewskiR. (2018). Oxidative stress in small vessel disease. Role of reactive species.Free Radic. Res.521–13. 10.1080/10715762.2017.1402304

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 176

  GrozioA.MillsK. F.YoshinoJ.BruzzoneS.SocialiG.TokizaneK.et al (2019). Slc12a8 is a nicotinamide mononucleotide transporter.Nat. Metab.147–57. 10.1038/s42255-018-0009-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 177

  GuarenteL. (2014). Linking DNA damage, NAD(⁺)/SIRT1, and aging.Cell. Metab.20706–707. 10.1016/j.cmet.2014.10.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 178

  GuareschiS.CovaE.CeredaC.CeroniM.DonettiE.BoscoD. A.et al (2012). An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1.Proc. Natl. Acad. Sci. U.S.A.1095074–5079. 10.1073/pnas.1115402109

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 179

  GueganC.VilaM.RosoklijaG.HaysA. P.PrzedborskiS. (2001). Recruitment of the mitochondrial-dependent apoptotic pathway in amyotrophic lateral sclerosis.J. Neurosci.216569–6576.

  • Pubmed Abstract
  • Google Scholar

• 180

  GuestJ.GrantR. (2016). Carotenoids and neurobiological health.Adv. Neurobiol.12199–228. 10.1007/978-3-319-28383-8_11

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 181

  GuilleA.BodorE. T.AhmedK.OffermannsS. (2008). Nicotinic acid: pharmacological effects and mechanisms of action.Annu. Rev. Pharmacol. Toxicol.4879–106. 10.1146/annurev.pharmtox.48.113006.094746

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 182

  GuoC.SunL.ChenX.ZhangD. (2013). Oxidative stress, mitochondrial damage and neurodegenerative diseases.Neural Regen. Res.82003–2014. 10.3969/j.issn.1673-5374.2013.21.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 183

  GuoY.ZhangL.LiF.HuC. P.ZhangZ. (2016). Restoration of sirt1 function by pterostilbene attenuates hypoxia-reoxygenation injury in cardiomyocytes.Eur. J. Pharmacol.77626–33. 10.1016/j.ejphar.2016.02.052

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 184

  GurneyM. E.CuttingF. B.ZhaiP.DobleA.TaylorC. P.AndrusP. K.et al (1996). Benefit of vitamin E, riuzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis.Ann. Neurol.39147–157. 10.1002/ana.410390203

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 185

  GustafsonD. R.Clare MorrisM.ScarmeasN.ShahR. C.SijbenJ.YaffeK.et al (2015). New perspectives on Alzheimer’s disease and nutrition.J. Alzheimers Dis.461111–1127. 10.3233/JAD-150084

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 186

  GyulkhandanyanA. V.FeeneyC. J.PennefatherP. S. (2003). Modulation of mitochondrial membrane potential and reactive oxygen species production by copper in astrocytes.J. Neurochem.87448–460.

  • Pubmed Abstract
  • Google Scholar

• 187

  HafnerA. V.DaiJ.GomesA. P.XiaoC. Y.PalmeiraC. M.RosenzweigA.et al (2010). Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy.Aging2914–923. 10.18632/aging.100252

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 188

  HaigisM. C.SinclairD. A. (2010). Mammalian sirtuins: biological insights and disease relevance.Annu. Rev. Pathol.5253–295. 10.1146/annurev.pathol.4.110807.092250

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 189

  HallE. D.AndrusP. K.OostveenJ. A.FleckT. J.GurneyM. E. (1998). Relationship of oxygen radical-induced lipid peroxidative damage to disease onset and progression in a transgenic model of familial ALS.J. Neurosci. Res.5366–77.

  • Pubmed Abstract
  • Google Scholar

• 190

  HalliwellB. (2012). Free radicals and antioxidants: updating a personal view.Nutr. Rev.70257–265. 10.1111/j.1753-4887.2012.00476.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 191

  HanS.ChoiJ. R.Soon-ShinK.KangS. J. (2012). Resveratrol upregulated heat shock proteins and extended the survival of G93A-SOD1 mice.Brain Res.5112–117. 10.1016/j.brainres.2012.09.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 192

  HarlanB. A.PeharM.SharmaD. R.BeesonG.BeesonC. C.VargasM. (2016). Enhancing NAD+ salvage pathway reverts the toxicity of primary astrocytes expressing amyotrophic lateral sclerosis-linked mutant SOD1.J. Biol. Chem.29110836–10846. 10.1074/jbc.M115.698779

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 193

  HarrazM. M.MardenJ. J.ZhouW.ZhangY.WilliamsA.SharovV. S.et al (2008). SOD1 mutations disrupt redox-sensitive.J. Clin. Invest.118659–670. 10.1172/JCI34060

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 194

  HeL.HeT.FarrarS.JiL.LiuT.MaX. (2017). Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species.Cell. Physiol. Biochem.44532–553. 10.1159/000485089

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 195

  HikosakaK.YakuK.OkabeK.NakagawaT. (2019). Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases.Nutr. Neurosci.71–13. 10.1080/1028415X.2019.1637504

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 196

  HodgkinsonV. L.LounsberryJ.MirianA.GengeA.BensteadT.BriembergH.et al (2018). Provincial differences in the diagnosis and care of amyotrophic lateral sclerosis.Can. J. Neurol. Sci.45652–659. 10.1017/cjn.2018.311

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 197

  HootenK. G.BeersD. R.ZhaoW.AppelS. H. (2015). Protective and toxic neuroinflammation in amyotrophic lateral sclerosis.Neurotherapeutics12364–375. 10.1007/s13311-014-0329-3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 198

  HouY.LautrupS.CordonnierS.WangY.CroteauD. L.ZavalaE.et al (2017a). NAD+ supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency.Proc. Natl. Acad. Sci. U.S.A.115E1876–E1885. 10.1073/pnas.1718819115

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 199

  HouY.SongH.CroteauD. L.AkbariM.BohrV. A. (2017b). Genome instability in Alzheimer disease.Mech. Ageing Dev.161(Pt A), 83–94. 10.1016/j.mad.2016.04.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 200

  HouY.XieG.MiaoF.DingL.MouY.WangI.et al (2014). Pterostilbene attenuates lipopolysaccharide-induced learning and memory impairment possibily via inhibiting microglia activation and protecting neuronal injury in mice.Prog. Neuropsychopharmacol. Biol. Psychiatry5492–102. 10.1016/j.pnpbp.2014.03.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 201

  HoutkooperR. H.CantóC.WandersR. J.AuwerxJ. (2010). The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways.Endocr. Rev.31194–223. 10.1210/er.2009-0026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 202

  HsiehH.YangC. M. (2013). Role of redox signaling in neuroinflammation and neurodegenerative diseases.Biomed. Res. Int.2013:484613. 10.1155/2013/484613

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 203

  HuaZ.RongT. (2016). Dietary polyphenols, oxidative stress and antioxidant and anti-inflammatory effects.Curr. Opin. Food Sci.833–42. 10.1016/j.cofs.2016.02.002

  • CrossRef
  • Google Scholar

• 204

  HuangJ. Y.HirscheyM. D.ShimazuT.HoL.VerdinE. (2010). Mitochondrial sirtuins.Biochim. Biophys. Acta18041645–1651. 10.1016/j.bbapap.2009.12.021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 205

  HuhnS.Kharabian MasoulehS.StumvollM.VillringerA.WitteV. (2015). Components of a Mediterranean diet and their impacto n cognitive functions in aging.Front. Aging Neurosci.7:132. 10.3389/fnagi.2015.00132

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 206

  HuiyongY.LibinX.PorterN. (2011). Free radical lipid peroxidation: mechanism and analysis.Chem. Rev.1115944–5972. 10.1021/cr200084z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 207

  IharaY.NobukuniK.TakataH.HayabaraT. (2005). Oxidative stress and metal content in blood and cerebrospinal fluid in amyotrophic lateral sclerosis patients with and without a Cu, Zn superoxide dismutase mutation.Neurol. Res.27105–108. 10.1179/016164105X18430

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 208

  IkawaM.OkazawaH.TsujikawaT.MuramatsuT.KishitaniT.KamisawaT.et al (2015). Increased oxidative stress is related to disease severity in the ALS motor cortex: a PET study.Neurology842033–2039. 10.1212/WNL.0000000000001588

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 209

  IkedaK.IwasakiY. (2015). Edaravone, a free radical scavenger, delayed symptomatic and pathological progression of motor neuron disease in the wobbler mouse.PLoS One10:e0140316. 10.1371/journal.pone.0140316

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 210

  ImaiS.GuarenteL. (2014). NAD+ and sirtuins in aging and disease.Trends Cell Biol.24464–471. 10.1016/j.tcb.2014.04.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 211

  IngreC.RoosP. M.PiehlF.KamelF.FangF. (2015). Risk factors for amyotrophic lateral sclerosis.Clin. Epidemiol.12181–193. 10.2147/CLEP.S37505

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 212

  InoueH.JiangX. F.KatayamaT.OsadaS.UmesonoK.NamuraS. (2003). Brain protection by reeratrol and fenofibrate against stroke requieres peroxsiome proliferator-activated receptor alpha in mice.Neurosci. Lett.352203–206.

  • Google Scholar

• 213

  IpP.ShardaP. R.CunninghamA.ChakrabarttyS.PandeV.ChakrabarttyA. (2017). Quercitrin and quercetin 3-β-d-glucoside as chemical chaperones for the A4V SOD1 ALS-causing mutant.Protein Eng. Des. Sel.30431–440. 10.1093/protein/gzx025

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 214

  IslamM. T. (2017). Oxidative stress and mitochondrial dysfunction-linked neurodegenerative disorders.Neurol. Res.3973–82. 10.1080/01616412.2016.1251711

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 215

  IsonakaR.HirumaH.KatakuraT.KawakamiT. (2011). Inhibition of superoxide dismutase selectively suppresses growth of rat spinal motor neurons: comparison with phosphorylated neurofilament-containing spinal neurons.Brain Res.142513–19. 10.1016/j.brainres.2011.09.046

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 216

  IsraelsonA.ArbelN.Da CruzS.IlievaH.YamanakaK.Shoshan-BarmatzV.et al (2010). Misfolded mutant SOD1 directly inhibits VDAC1 conductance in a mouse model of inherited ALS.Neuron67575–587. 10.1016/j.neuron.2010.07.019

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 217

  IversonS. L.OrreniusS. (2004). The cardiolipin-cytochrome c interaction and the mitochondrial regulation of apoptosis.Arch. Biochem. Biophys.42337–46.

  • Pubmed Abstract
  • Google Scholar

• 218

  JacksonC.Heiman-PattersonT.KittrellP.BaranovskyT.McananamaG.BowerL.et al (2019). Radicava (edaravone) for amyotrophic lateral sclerosis: US experience at 1 year after launch.Amyotroph. Lateral Scler. Frontotemporal. Degener.201–6. 10.1080/21678421.2019.1645858

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 219

  JacobS.PoegglerB.WeishauptJ. H.SirénA. L.HardelandR.BährM.et al (2002). Melatonin as a candidate compound for neuroprotection in amyotrophic lateral sclerosis (ALS): high tolerability of daily oral melatonin administration in ALS patients.J. Pineal Res.33186–187.

  • Google Scholar

• 220

  JaiswalM. K. (2017). Riluzole but not melatonin ameliorates acute motor neuron degeneration and moderately inhibits sod1-mediated excitotoxicity induced disrupted mitochondrial ca²⁺ signaling in amyotrophic lateral sclerosis.Front. Cell. Neurosci.10:295. 10.3389/fncel.2016.00295

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 221

  JennerP. (2003). Oxidative stress in Parkinson’s disease.Ann. Neurol.53(Suppl. 3), S26–S36.

  • Google Scholar

• 222

  JeongJ. K.MoonM. H.BaeB. C.LeeY. J.SeolJ. W.KangH. S.et al (2012). Autophagy induced by resveratrol prevents human prion protein-mediated neurotoxicity.Neurosci. Res.7399–105. 10.1016/j.neures.2012.03.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 223

  JęśkoH.WencelP.StrosznajderR. P.StrosznajderJ. B. (2017). Sirtuins and their roles in brain aging and neurodegenerative disorders.Neurochem. Res.42876–890. 10.1007/s11064-016-2110-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 224

  JhaN.RyuJ. J.ChoiE. H.KaushikN. K. (2017). Generation and role of reactive oxygen and nitrogen species induced by plasma, lasers, chemical agents, and other systems in dentistry.Oxid. Med. Cell. Longev.2017:7542540. 10.1155/2017/7542540

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 225

  JiangH.TianX.GuoY.DuanW.BuH.LiC. (2011). Activation of nuclear factor erythroid 2-related factor 2 cytoprotective signaling by curcumin protect primary spinal cord astrocytes against oxidative toxicity.Biol. Pharm. Bull.341194–1197.

  • Pubmed Abstract
  • Google Scholar

• 226

  JieL.WulijiO.WeiL.Zhi-GangJ.HosseinA. G. (2013). Oxidative stress and neurodegenerative disorders.Int. J. Mol. Sci.1424438–24475. 10.3390/ijms141224438

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 227

  JinQ.CaiY.LiS.LiuH.ZhouX.LuC.et al (2017). Edaravone –encapsuled agonistic micelles rescue ischemic brain tissue by tuning blood-brain barrier permability.Theranostics7884–898. 10.7150/thno.18219

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 228

  JinY.OhK.OhS. I.BaekH.KimS. H.ParkY. (2014). Dietary intake of fruits and beta-carotene is negatively associated with amyotrophic lateral sclerosis risk in Koreans: a case-control study.Nutr. Neurosci.17104–108. 10.1179/1476830513Y.0000000071

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 229

  JohnsonS.ImaiS. I. (2018). NAD + biosynthesis, aging, and disease.F1000Research7:132. 10.12688/f1000research.12120.1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 230

  JohnsonW. M.Wilson-DelfosseA. L.MieyalJ. J. (2012). Dysregulation of glutathione homeostasis in neurodegenerative diseases.Nutrients41399–1440. 10.3390/nu4101399

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 231

  JosephJ. A.FisherD. R.ChengV.RimandoA. M.Shukitt-HaleB. (2008). Cellular and behavioral effects of stilbene resveratrol analogues: implications for reducing the deleterious effects of aging.J. Agric. Food Chem.5610544–10551. 10.1021/jf802279h

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 232

  JosephJ. A.Shukitt-HaleB.BrewerG. J.WeikelK. A.WilhelminaK.FisherD. R. (2011). Differential protection among fractionated blueberry polyphenolic families against DA-, Aβ42 and LPS-induced decrements in Ca²⁺ buffering in primary hippocampal cells.J. Agric. Food Chem.588196–8204. 10.1021/jf100144y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 233

  JouM. J. (2008). Pathophysiological and pharmacological implications of mitochondria-targeted reactive oxygen species generation in astrocytes.Adv. Drug Deliv. Rev.601512–1526. 10.1016/j.addr.2008.06.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 234

  JulienJ. P. (2007). ALS: astrocytes move in as deadly neighbors.Nat. Neurosci.10535–537. 10.1038/nn0507-535

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 235

  JungC.HigginsC. M.XuZ. (2002). Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis.J. Neurochem.83535–545.

  • Pubmed Abstract
  • Google Scholar

• 236

  JuríkováT.MlcekJ.SochorJ.HegedusováA. (2015). Polyphenols and their mechanism of action in allergic immune response.Glob. J. Allergy137–39. 10.17352/2455-8141.000008

  • CrossRef
  • Google Scholar

• 237

  KapetanovicJ. M.MuzzioM.HuangZ.ThompsonT. N.McCormickD. L. (2011). Pharmacokinetics, oral bioavailability, and metabolic profile of resveratrol and its dimethylether analog, pterostilbene, in rats.Cancer Chemother. Pharmacol.68593–601. 10.1007/s00280-010-1525-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 238

  KaramC.YiJ.XiaoY.DhakalK.ZhangL.LiX.et al (2017). Abscence of physiological Ca 2+ transients is an initial trigger for mitochondrial dysfunction in skeletal muscle following denervation.Skelet. Muscle7:6. 10.1186/s13395-017-0123-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 239

  KaufmannP.ThompsonJ. L.LevyG.BuchsbaumR.ShefnerJ.KrivickasL. S.et al (2009). Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III.Ann. Neurol.66235–244. 10.1002/ana.21743

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 240

  KawaharaY.ItoK.SunH.AizawaH.KanazawaI.KwakS. (2004). Glutamate receptors: RNA editing and death of motor neurons.Nature427:801. 10.1038/427801a

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 241

  KayeW. E.WagnerL.WuR.MethaP. (2018). Evaluating the completeness of the national ALS registry, United States.Amyotroph. Lateral Scler. Frontotemporal. Degener.19112–117. 10.1080/21678421.2017.1384021

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 242

  KehrerJ. P.KlotzL. O. (2015). Free radicals and related reactive species as mediators of tissue injury and disease: implications for health.Crit. Rev. Toxicol.45765–798. 10.3109/10408444.2015.1074159

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 243

  KidaY.GoligorskyM. S. (2016). Sirtuins, cell senescence, and vascular aging.Can. J. Cardiol.32634–641. 10.1016/j.cjca.2015.11.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 244

  KilloyK. M.HarlanB. A.PeharM.HelkeK. L.JohnsonJ. A.VargasM. R. (2018). Decreased glutathione levels cause overt motor neuron degeneration in hSOD1WT over-expressing mice.Exp. Neurol.302129–135. 10.1016/j.expneurol.2018.01.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 245

  KimD.NguyenM. D.DobbinM. M.FischerA.SananbenesiF.RodgersJ. T.et al (2007). SIRT1 deacetylase protects against neurodegeneration in models for Alzheimer’s disease and amyotrophic lateral sclerosis.EMBO J.263169–3179. 10.1038/sj.emboj.7601758

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 246

  KimD. S.KimJ. Y.HanY. (2012). Curcuminoids in neurodegenerative diseases.Recent Pat. CNS Drug Discov.7184–204.

  • Pubmed Abstract
  • Google Scholar

• 247

  KimG. H.KimJ. E.RhieS. J.YoonS. (2015). The role of oxidative stress in neurodegenerative diseases.Exp. Neurobiol.24325–340. 10.5607/en.2015.24.4.325

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 248

  KimJ. S.HaT. Y.AhnJ.KimH. J.KimS. (2009). Pterostilbene from Vitis coignetiae rotect H2O2-induced inhibition of gap junctional intercelular communication in rat liver cell line.Food Chem. Toxicol.47404–409. 10.1016/j.fct.2008.11.038

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 249

  KimS. H.HenkelJ. S.BeersD. R.SengunI. S.SimpsonE. P.GoodmanJ. C.et al (2003). PARP expression is increased in astrocytes but decreased in motor neurons in the spinal cord of sporadic ALS patients.J. Neuropathol. Exp. Neurol.6288–103.

  • Pubmed Abstract
  • Google Scholar

• 250

  KohS. H.KwonH.KimK. S.KimJ.KimM. H.YuH. J.et al (2004). Epigallocatechin gallate prevents oxidative-stress-induced death of mutant Cu/Zn-superoxide dismutase (G93A) motoneuron cells by alteration of cell survival and death signals.Toxicology202213–225. 10.1016/j.tox.2004.05.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 251

  KohS. H.LeeS. M.KimH. Y.LeeK. Y.KimH. T.KimJ.et al (2006). The effect of epigallocatechin gallate on suppressing disease progression of ALS model mice.Neurosci. Lett.395103–107. 10.1016/j.neulet.2005.10.056

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 252

  KorkmazO. T.AytanN.CarrerasI.ChoiJ. K.KowallN. W.JenkinsB. G.et al (2014). 7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis.Neurosci. Lett.566286–291. 10.1016/j.neulet.2014.02.058

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 253

  KörnerS.BöseltS.ThauN.RathK. J.DenglerR.PetriS. (2013). Differential sirtuin expression patterns in amyotrophic lateral sclerosis (ALS) postmortem tissue: neuroprotective or neurotoxic properties of sirtuins in ALS?Neurodegener. Dis.11141–152. 10.1159/000338048

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 254

  KosuruR.RaiU.PrakashS.SinghA.SinghS. (2016). Promising therapeutical potential of pterostilbene and its mechanistic insight based on preclinical evidence.Eur. J. Pharmacol.789229–243. 10.1016/j.ejphar.2016.07.046

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 255

  KrinskyN. I.JohnsonE. J. (2005). Carotenoid actions and their relation to health and disease.Mol. Aspects Med.26459–516. 10.1016/j.mam.2005.10.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 256

  KrishnarajR. N.KumariS. S.MukhopadahyayS. S. (2016). Antagonistic molecular interactions of photosynthetic pigments with molecular disease targets: a new approach to treat AD and ALS.J. Recept. Signal Transduct. Res.3667–71. 10.3109/10799893.2015.1024851

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 257

  KulikovaV. A.GromykoD. V.NikiforovA. A. (2018). The regulatory role of NAD in human and animal cells.Biochemistry83800–812. 10.1134/S0006297918070040

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 258

  KumarS.PandeyA. K. (2015). Free radicals: health implications and their mitigation by herbals.Br. J. Med. Med. Res.7438–457. 10.9734/BJMMR/2015/16284

  • CrossRef
  • Google Scholar

• 259

  KupisW.PalygaJ.TomalE.NiewiadomskaE. (2016). The role of sirtuins in cellular homeostasis.J. Physiol. Biochem.72371–380. 10.1007/s13105-016-0492-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 260

  KurtishiA.RosenB.PatilK. S.AlvesG. W.MollerS. G. (2018). Cellular proteostasis in neurodegeneration.Mol. Neurobiol.563676–3689. 10.1007/s12035-018-1334-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 261

  KutilZ.PribylovaM.TemmlV.SchusterD.MarsikP.SusimamaniE.et al (2015). Effect of dietary stilbenes on 5-lipoxygenase and cyclooxygenase activities in vitro.Int. J. Food Prop.181471–1477. 10.1080/10942912.2014.903416

  • CrossRef
  • Google Scholar

• 262

  Lamuela-RaventósR. M.Vallverdú-QueraltA.JáureguiO.Martínez-HuélamoP.Quifer-RadaP. (2014). Improved characterization of polyphenols using liquid chromatography.Polyphenols Plants14261–292. 10.1016/B978-0-12-397934-6.00014-0

  • CrossRef
  • Google Scholar

• 263

  LangeK. W.LiS. (2018). Resveratrol, pterostilbene and dementia.Biofactors4483–90. 10.1002/biof.1396

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 264

  LanskaD. J. (2012). The discovery of niacin, biotin, and panthotenic acid.Ann. Nutr. Metab.61246–253. 10.1159/000343115

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 265

  LaudatiG.MascoloL.GuidaN.SirabellaR.PizzorussoV.BruzznatiS.et al (2019). Resveratrol treatment reduces the vulnerability of SH-SY5Y cells and cortical neurons overexpressing SOD1-G93A to Thimerosal toxicity through SIRT1/DREAM/PDYN pathway.Neurotoxicology716–15. 10.1016/j.neuro.2018.11.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 266

  LautrupS.SinclairD. A.MattsonM. P.FangE. F. (2019). NAD+ in brain aging and neurodegenerative disorders.Cell Metab.30630–655. 10.1016/j.cmet.2019.09.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 267

  LeeY. A.YunB. H.KimS. K.MargolinY.DedonP. C.GeacintovN. E.et al (2007). Mechanisms of oxidation of guanine in DNA by carbonate radical anion, a decomposition product of nitrosoperoxycarbonate.Chemistry134571–4581. 10.1002/chem.200601434

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 268

  LevitesY.AmitT.YoudimM. B.MandelS. (2002). Involvement of protein kinase C activation and cell survival/cell cycle genes in green tea polyphenol (-)-epigallocatechin 3-gallate neuroprotective action.J. Biol. Chem.27730574–30580. 10.1074/jbc.M202832200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 269

  LiD.SongT.YangL.WangX.YangC.JiangY. (2016). Neuroprotective actions of pterostilbene on hypoxic-ischemic brain damage in neonatal rats through upregulation of heme oxygenase-1.Int. J. Dev. Neurosci.5422–31. 10.1016/j.ijdevneu.2016.08.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 270

  LiJ.LiW.SuJ.LiuW.AlturaB. T.AlturaB. M. (2003). Hydrogen peroxide induces apoptosis in cerebral vascular smooth muscle cells: possible relation to neurodegenerative diseases and strokes.Brain Res. Bull.62101–106.

  • Pubmed Abstract
  • Google Scholar

• 271

  LiL.SunQ.LiY.YangY.ChangT.ManM.et al (2015). Overexpression of SIRT1 induced by resveratrol and inhibitor of miR-204 suppresses activation and proliferation of microglia.J. Mol. Neurosci.56858–867. 10.1007/s12031-015-0526-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 272

  LiQ.ChenL.LiuX.LiX.CaoY.BaiY.et al (2018). Pterostilbene inhibits amyloid-β-induced neuroinflammation in a microglia cell line by inactivating the NLRP3/caspase-1 inflammasome pathway.J. Cell. Biochem.1197053–7062. 10.1002/jcb.27023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 273

  LiQ.SpencerN. Y.PantazisN. J.EngelhardtJ. F. (2011). Alsin and SOD1(G93A) proteins regulate endosomal reactive oxygen specie production by glial cells and proinflammatory pathways responsable for neurotoxicity.J. Biol. Chem.28640151–40162. 10.1074/jbc.M111.279711

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 274

  LiY.QuiangX.LiY.YangX.LuoL.XiaoG.et al (2016). Pterostilbene-O-acetamidoalkylbenzylamines derivatives as novel dual inhibitors of cholinesterase with anti-β-amyloid aggregation and antioxidant properties for the treatment of Alzheimer’s disease.Bioorg. Med. Chem. Lett.262035–2039. 10.1016/j.bmcl.2016.02.079

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 275

  LiY. R.LiS.LinC. C. (2018). Effect of resveratrol and pterostilbene on aging and logenvity.Biofactors4469–82. 10.1002/biof.1400

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 276

  LiangH.WardW. F. (2006). PGC-1alpha: a key regulator of energy metabolism.Adv. Physiol. Educ.30145–151. 10.1152/advan.00052.2006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 277

  LiguoriI.RussoG.CurcioF.BulliG.AranL.Della-MorteD.et al (2018). Oxidative stress, aging and diseases.Clin. Interv. Aging13757–772. 10.2147/CIA.S158513

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 278

  LinM. T.BealM. F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases.Nature443787–795. 10.1038/nature05292

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 279

  LinY. J.DingY.WuJ.NingB. T. (2016). Pterostilbene as treatment for severe acute pancreatitis.Genet. Mol. Res.15:15038330. 10.4238/gmr.15038330

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 280

  LiochevS. I. (2013). Reactive oxygen species and the free radical theory of aging.Free Radic. Biol. Med.601–4. 10.1016/j.freeradbiomed.2013.02.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 281

  LiuJ.LilloC.JonssonP. A.Vande VeldeC.WardC. M.MillerT. M.et al (2004). Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria.Neuron435–17. 10.1016/j.neuron.2004.06.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 282

  LiuW.ZhaiY.HengX.CheF. Y.ChenW.SunD.et al (2016). Oral bioavailability of curcumin: problems and advancements.J. Drug Target.24694–702. 10.3109/1061186X.2016.1157883

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 283

  LiuX.YangX.HanL.YeF.LiuM.FanW.et al (2017). Pterostilbene alleviates polymicrobial sepsis-induced liver injury: possible role of SIRT1signaling.Int. Immunopharmacol.4950–59. 10.1016/j.intimp.2017.05.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 284

  LoefflerJ. P.PicchiarelliG.DupuisL.Gonzalez de AguilarJ. L. (2016). The role of skeletal muscle in amyotrophic lateral sclerosis.Brain Pathol.26227–236. 10.1111/bpa.12350

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 285

  LoGerfoA.ChicoL.BorgiaL.PetrozziL.RocchiA.D’AmelioA.et al (2014). Lack of association between nuclear factor erythroid-derived 2-like 2 promoter gene polymorphisms and oxidative stress biomarkers in amyotrophic lateral sclerosis patients.Oxid. Med. Cell. Longev.2014:432626. 10.1155/2014/432626

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 286

  LoizzoS.PieriM.FerriA.CarrìM. T.ZonaC.FortunaA.et al (2010). Dynamic NAD(P)H post-synaptic autofluorescence signals for the assessment of mitochondrial function in a neurodegenerative disease: monitoring the primary motor cortex of G93A mice, an amyotrophic lateral sclerosis model.Mitochondrion10108–114. 10.1016/j.mito.2009.11.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 287

  LongeckerM. P.KamelF.UmbachD. M.MunsatT. L.ShefnerJ. M.LandsellL. W.et al (2000). Dietary intake of calcium, magnesium and antioxidants in relation to risk of amyotrophic lateral sclerosis.Neuroepidemiology19210–216. 10.1159/000026258

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 288

  López-OtínC.BlascoM. A.PartridgeL.SerranoM.KroemerG. (2013). The hallmarks of aging.Cell1531194–1217. 10.1016/j.cell.2013.05.039

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 289

  LuJ.DuanW.GuoY.JiangH.LiZ.HuangJ.et al (2012). Mitochondrial dysfunction in human TDP-43 transfected NSC34 cell lines and the protective effect of dimethoxy curcumin.Brain Res. Bull.89185–190. 10.1016/j.brainresbull.2012.09.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 290

  MackenzieI. R. A.RademakersR. (2008). The role of TDP-43 in amyotrophic lateral sclerosis and frontotemporal dementia.Curr. Opin. Neurol.21693–700. 10.1097/WCO.0b013e3283168d1d

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 291

  MagranéJ.CortezC.GanW. B.ManfrediG. (2014). Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models.Hum. Mol. Genet.231413–1424. 10.1093/hmg/ddt528

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 292

  MancusoR.del ValleJ.ModolL.MartinezA.Granado-SerranoA. B.Ramírez-NúñezO.et al (2014a). Resveratrol improves motoneuron function and extends survival in SOD1(G93A) ALS mice.Neurotherapeutics11419–432. 10.1007/s13311-013-0253-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 293

  MancusoR.del ValleJ.MorellM.PallásM.OstaR.NavarroX. (2014b). Lack of synergistic effect of resveratrol and sigma-1 receptor agonist (PRE-084) in SOD1G93A ALS mice: overlapping effects or limited therapeutic opportunity?Orphanet J. Rare Dis.9:78. 10.1186/1750-1172-9-78

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 294

  MandelS.ReznichenkoL.AmitT.YoudimM. B. (2003). Green tea polyphenol (-)-epigallocatechin-3-gallate protects rat PC12 cells from apoptosis induced by serum withdrawal independent of P13-Akt pathway.Neurotox. Res.5419–424.

  • Pubmed Abstract
  • Google Scholar

• 295

  MandelS. A.Avramovich-TiroshY.ReznichenkoL.ZhengH.WeinrebO.AmitT.et al (2005). Multifunctional activities of green tea catechins in neuroprotection. Modulation of cell survival genes, iron-dependent oxidative stress and PKC signaling pathway.Neurosignals1446–60. 10.1159/000085385

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 296

  MansuriM. L.PariharP.SolankiI.PariharM. S. (2014). Flavonoids in modulation of cell survival signalling pathways.Genes Nutr.9:400. 10.1007/s12263-014-0400-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 297

  MantillaC. B.ErmilovL. G. (2012). The novel TrkB receptor agonist 7,8-dihydroxyflavone enhances neuromuscular transmission.Muscle Nerve45274–276. 10.1002/mus.22295

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 298

  MarinB.BoumedineF.LogroscinoG.CouratierP.BabronM. C.LeuteneggerA. L.et al (2017). Variation in worldwide incidence of amyotrophic lateral sclerosis: a meta-analysis.Int. J. Epidemiol.4657–74. 10.1093/ije/dyw061

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 299

  MartensC. R.DenmanB. A.MazzoM. R.ArmstrongM. L.ReisdorphN.McQueenM. B.et al (2018). Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults.Nat. Commun.9:1286. 10.1038/s41467-018-03421-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 300

  MartinL. J. (2010). Mitochondrial patohiology in Parkinson’s disease and amyotrophic lateral sclerosis.J. Alzheimers Dis.20(Suppl. 2), S335–S356. 10.3233/JAD-2010-100348

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 301

  MassaadC. A.KlannE. (2011). Reactive oxygen species in the regulation of synaptic plasticity and memory.Antioxid. Redox. Signal.142013–2054. 10.1089/ars.2010.3208

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 302

  MatthewsR. T.YangL.BrowmneS.BaikM.BealM. F. (1998). Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects.Proc. Natl. Acad. Sci. U.S.A.958892–8897.

  • Pubmed Abstract
  • Google Scholar

• 303

  MattiazziM.D’AurelioM.GajewskiC. D.MartushovaK.KiaeiM.BealM. F.et al (2002). Mutated human SOD1 causes dysfunction of oxidative phosphorylation in mitocondria of transgenic mice.J. Biol. Chem.27729626–29633. 10.1074/jbc.M203065200

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 304

  McCombeP. A.HendersonR. D. (2010). Effects of gender in amyotrophic lateral sclerosis.Gend. Med.7557–570. 10.1016/j.genm.2010.11.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 305

  MehtaP.KayeW.RaymondJ.WuR.LarsonT.PunjaniR.et al (2018). Prevalence of amyotrophic lateral sclerosis - United States, 2014.Morb. Mortal. Wkly. Rep.67216–218. 10.15585/mmwr.mm6707a3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 306

  MendelsohnA. R.LarrickJ. W. (2014). Partial reversal of skeletal muscle aging by restoration of normal NAD+ levels.Rejuvenation Res.1762–69. 10.1089/rej.2014.1546

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 307

  MendelsohnA. R.LarrickJ. W. (2017). The NAD+/PARP1/SIRT1 axis in aging.Rejuvenation Res.20244–247. 10.1089/rej.2017.1980

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 308

  MenziesF. M.InceP. G.ShawP. J. (2002). Mitochondrial involvement damage in patients with sporadic amyotrophic lateral sclerosis.Neurochem. Int.40543–551. 10.1016/S0197-0186(01)00125-5

  • CrossRef
  • Google Scholar

• 309

  MergenthalerP.LindauerU.DienelG. A.MeiselA. (2013). Sugar for the brain: the role of glucose in physiological and pathological brain function.Trends Neurosci.36587–597. 10.1016/j.tins.2013.07.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 310

  Michal-FreedmanD.KunclR. W.WeinsteinS. J.MalilaN.VirtamoJ.AlbanesD. (2013). Vitamin E serum levels and controlled supplementation and risk of amyotrophic lateral sclerosis.Amyotroph. Lateral Scler. Frontotemporal. Degener.14246–251. 10.3109/21678421.2012.745570

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 311

  MikstackaR.RimandoA. M.IgnatowiczE. (2010). Antioxidant effect of trans-resveratrol, pterostilbene, quercetin and their combinations in human erythrocytes in vitro.Plant Foods Hum. Nutr.6557–63. 10.1007/s11130-010-0154-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 312

  MilatovicD.MontineT. J.AschnerM. (2011). Measurement of isoprostanes as markers of oxidative stress.Methods Mol. Biol.758195–204. 10.1007/978-1-61779-170-3_13

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 313

  MillerA. A.BudzynK.SobeyG. G. (2010). Vascular dysfunction in cerebrovascular disease: mechanisms and therapeutic intervention.Clin. Sci.1191–17. 10.1042/CS20090649

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 314

  MillerE.MorelA.SasoL.SalukJ. (2014). Isoprostanes and neuroprostanes as biomarkers of oxidative stress in neurodegenerative diseases.Oxid. Med. Cell. Longev.2014:572491. 10.1155/2014/572491

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 315

  MillerM. G.Shukitt-HaleB. (2012). Berry fruit enhances beneficial signaling in the brain.J. Agric. Food. Chem.605709–5715. 10.1021/jf2036033

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 316

  MillerR. G.MitchellJ. D.MooreD. H. (2012). Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND).Cochrane Database Syst. Rev.14:CD001447. 10.1002/14651858.CD001447.pub3

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 317

  MilneG. L.SanchezS. C.MusiekE. S.MorrowJ. D. (2007). Quantification of F2-isoprostanes as biomarker of oxidative stress.Nat. Protoc.2221–226. 10.1038/nprot.2006.375

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 318

  MintoC.VecchioM. G.LamprechtM.GregoriD. (2017). Definition of a tolerable upper intake level of niacin: a systematic review and meta-analysis of the doe-dependent effects of nicotinamide and nicotinic acid supplementation.Nutr. Rev.75471–490. 10.1093/nutrit/nux011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 319

  MitchellJ.BorasioG. (2007). Amyotrophic lateral sclerosis.Lancet3692031–2041. 10.1016/S0140-6736(07)60944-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 320

  MitsumotoH.SantellaR. M.XinhauL.BogdanovM.ZipprichJ.Hui-ChenW.et al (2008). Oxidative Stress biomarkers in sporadic ALS.Amyotroph. Lateral Scler.9177–183. 10.1080/17482960801933942

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 321

  MiyamotoN.MakiT.PhamL. D.HayakawaK.SeoJ. H.MandevilleE. T.et al (2013). Oxidative stress interferes with White matter renewal after prolonged cerebral hypoperfusion in mice.Stroke443516–3521. 10.1161/STROKEAHA.113.002813

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 322

  MolinaJ. A.De BustosF.Jiménez-JiménezF. J.Gómez-EscalonillaC.García-RedondoA.EstebanJ.et al (2000). Serum levels of coenzyme Q10 in patients with amyotrophic lateral sclerosis.J. Neural Transm.1071021–1026. 10.1007/s007020070050

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 323

  MoonY.ChoiY. J.KimJ. O.HanS. H. (2018). Muscle profile and cognition in patients with Alzheimer’s disease dementia.Neurol. Sci.391861–1866. 10.1007/s10072-018-3505-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 324

  MoratóL.BertiniE.VerriginiD.ArdissoneA.RuizM.FerrerI.et al (2014). Mitochondrial dysfunction in central nervous system white matters disorders.Glia621878–1894. 10.1002/glia.22670

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 325

  MoreiraP. I.DuarteA. I.SantosM. S.RegoA. C.OliveiraC. R. (2009). An integrative view of the role of oxidative stress, mitocondria and insulin in Alzheimer’s disease.J. Alzheimers. Dis.16741–761. 10.3233/JAD-2009-0972

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 326

  MouchiroudL.HoutkooperR. H.MoullanN.KatsyubaE.RyuD.CantóD.et al (2013). The NAD(+)/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling.Cell154430–441. 10.1016/j.cell.2013.06.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 327

  MoujalledD.GrubmanA.AcevedoK.YangS.KeY. D.MoujalledD. M.et al (2017). TDP-43 mutations causing amyotrophic lateral sclerosis are associated with altered expression of RNA-binding protein hnRNP K and affect the Nrf2 antioxidant pathway.Hum. Mol. Genet.261732–1746. 10.1093/hmg/ddx093

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 328

  MurphyM. P. (2009). How mitochondria produce reactive oxygen species.Biochem. J.4171–13. 10.1042/BJ20081386

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 329

  NagaseM.YamamotoY.MiyazakiY.YoshinoH. (2016). Increased oxidative stress in patients with amyotrophic lateral sclerosis and the effect of edaravone administration.Redox. Rep.21104–112. 10.1179/1351000215Y.0000000026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 330

  NaikB.NirwaneA.MajumdarA. (2017). Pterostilbene ameliorates intracerebroventricular streptozotocin induced memory decline in rats.Cogn. Neurodyn.1135–49. 10.1007/s11571-016-9413-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 331

  NealM.RichardsonJ. R. (2018). Time to get personal: a framework for personalized targeting of oxidative stress in neurotoxicity and neurodegenerative disease.Curr. Opin. Toxicol.7127–132. 10.1016/j.cotox.2018.02.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 332

  NevesA. R.LúcioM.LimaJ. L. C.ReisS. (2012). Resveratrol in medicinal chemistry: a critical review of its pharmacokinetics, drug-delivery, and membrana interactions.Curr. Med. Chem.191663–1681.

  • Pubmed Abstract
  • Google Scholar

• 333

  NieG.GaoY.ZhaoB. (2002). Protective effects of green tea polyphenols and their major component, (-)-epigallocatechin-3-gallate (EGCG), on 6-hydroxydopamine-induced apoptosis in PC12 cells.Redox. Rep.7171–177. 10.1179/135100002125000424

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 334

  NiedzielskaE.SmagaI.GawlikM.MoniczewskiA.StankowiczP.PeraJ.et al (2016). Oxidative stress in neurodegenerative diseases.Mol. Neurobiol.534094–4125. 10.1007/s12035-015-9337-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 335

  NiedzwieckiA.RoomiM. W.KalinovskyT.RathM. (2016). Anticancer efficacy of polyphenols and their combinations.Nutrients8:552. 10.3390/nu8090552

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 336

  NievesJ. W.GenningsC.Factor- LitvakP.HupfJ.SingletonJ.SharfV.et al (2016). Association between dietary intake and function in amyotrophic lateral sclerosis.JAMA Neurol.731425–1432. 10.1001/jamaneurol.2016.3401

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 337

  NikiE. (2014). Biomarkers in lipid peroxidation in clinical material.Biochim. Biophys. Acta1840809–817. 10.1016/j.bbagen.2013.03.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 338

  NikiforovA.DolleC.NiereM.ZieglerM. (2011). Pathways and subcellular compartmentation of NAD biosynthesis in human cells: from entry of extracelullar precursors to mitochondrial NAD generation.J. Biol. Chem.28621767–21778. 10.1074/jbc.M110.213298

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 339

  Nikolic-KokicA.StevicZ.BlagojevicD.DavidovicB.JonesD. R.SpasicM. B. (2006). Alterations in anti-oxidative defence enzymes in erythrocytes sporadic amyotrophic lateral sclerosis (SALS) and familial ALS patients.Clin. Chem. Lab. Med.44589–593. 10.1515/CCLM.2006.111

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 340

  NisarN.LiL.LuS.KhinN. C.PogsonB. J. (2015). Carotenoid metabolism in plants.Mol. Plant868–82. 10.1016/j.molp.2014.12.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 341

  NizynskiB.DzwolakW.NieznanskiK. (2017). Amyloidogenesis of Tau protein.Protein Sci.262126–2150. 10.1002/pro.3275

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 342

  NourY.NawalA.MajedJ.ChantalM. (2018). The immunomodulatory and anti-inflammatory role of polyphenols.Nutrients10:1618. 10.3390/nu10111618

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 343

  NunomuraA.HondaK.TakedaA.HiraiK.ZhuX.SmithM. A.et al (2006). Oxidative damage to RNA in neurodegenerative diseases.J. Biomed. Biotechnol.2006:82323. 10.1155/JBB/2006/82323

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 344

  OakeyL. A.FletcherR. S.ElhassanY. S.CartwrightD. M.DoigC. L.GartenA.et al (2018). Metabolic tracing reveals novel adaptations to skeletal muscle cell energy production pathways in response to NAD + depletion.Wellcome Open Res.3:147. 10.12688/wellcomeopenres.14898.2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 345

  OberstadM.StielerJ.SimpongD. L.RömußU.UrbanN.SchaeferM.et al (2018). TDP-43 self-interaction is modulated by redox-active compounds Auranofin, Chelerythrine and Riluzole.Sci. Rep.8:2248. 10.1038/s41598-018-20565-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 346

  O’CallaghanC.VassilopoulosA. (2017). Sirtuins at the crossroads of stemness, aging, and cáncer.Aging Cell161208–1218. 10.1111/acel.12685

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 347

  OkadaM.YamashitaS.UevamaH.IshizakiM.MaedaY.AndoY. (2018). Long-term effects of edaravone on survival of patients with amyotrophic lateral sclerosis.Neurol. Sci.1111–14. 10.1016/j.ensci.2018.05.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 348

  OkamotoK.KihiraT.KobashiG.WashioM.SasakiS.YokoyamaT.et al (2009). Fruit and vegetable intake and risk of amyotrophic lateral sclerosis in Japan.Neuroepidemiology32251–256. 10.1159/000201563

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 349

  OlivieroF.ScanuA.Zamudio-CuevasY.PunziL.SpinellaP. (2018). Anti-inflammatory effects of polyphenols in arthritis.J. Sci. Food Agric.981653–1659. 10.1002/jsfa.8664

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 350

  OrrellR. W.LaneJ. M.RossM. A. (2004). Antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease.Cochrane Database Syst. Rev.18:CD002829. 10.1002/14651858.CD002829.pub2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 351

  PanL.YoshiiY.OtomoA.OgawaH.IwasakiY.ShangH. F.et al (2012). Different human copper-zinc superoxide dismutase mutants, SOD1, and SOD1 exert distinct harmful effect on gross phenotype in mice.PLoS One7:e33409. 10.1371/journal.pone.0033409

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 352

  PanM. H.ChangY. H.TsaiM. L.LaiC. S.HoS. Y.BadmaevV.et al (2008). Pterostilbene suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages.J. Agric. Food Chem.567502–7509. 10.1021/jf800820y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 353

  Pandi-PerumalS. R.BaHammamA. S.BrownG. M.SpenceD. W.BhartiV. K.KaurC.et al (2013). Melatonin antioxidative defense: therapeutical implications for aging and neurodegenerative processes.Neurotox. Res.23267–300. 10.1007/s12640-012-9337-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 354

  PanickarK. S.PolanskyM. M.AndersonR. A. (2009). Green tea polyphenols attenuate glial swelling and mitochondrial dysfunction following oxygen-glucose deprivation in cultures.Nutr. Neurosci.12105–113. 10.1179/147683009X423300

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 355

  PapadimitriouD.Le VercheV.JacquierA.IkizB.PrzedborskiS.ReD. B. (2010). Inflammation in ALS and SMA: sorting out the good from the evil.Neurobiol. Dis.37493–502. 10.1016/j.nbd.2009.10.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 356

  ParakhS.SpencerD. M.HalloranM. A.SooK. Y.AtkinJ. D. (2013). Redox regulation in amyotrophic lateral sclerosis.Oxid. Med. Cell. Longev.2013:408681. 10.1155/2013/408681

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 357

  ParkJ. H.HongY. H.KimH. J.KimS. M.ParkK. S.SungJ. J.et al (2007). Pyruvate slows disease progression in a G93A SOD1 mutant transgenic mouse model.Neurosci. Lett.413265–269. 10.1016/j.neulet.2006.11.058

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 358

  PaulS.RimandoA. M.LeeH. J.JiY.ReddyB. S.SuhN. (2009). Anti-inflammatory action of pterostilbene is mediated through the p38 mitogen-activated protein kinase pathway in colon cancer cells.Cancer Prev. Res.2650–657. 10.1158/1940-6207.CAPR-08-0224

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 359

  PayneB. A.ChinneryP. F. (2015). Mitochondrial dysfunction in aging: much progress but many unresolved questions.Biochim. Biophys. Acta18471347–1353. 10.1016/j.bbabio.2015.05.022

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 360

  PeharM.BeesonG.BeesonC. C.JohnsonJ. A.VargasM. R. (2014). Mitochondria-targeted catalase reverts the neurotoxicity of h SOD1G(9)(3) A astrocytes without extending the survival of ALS-linked mutant hSOD1 mice.PLoS One9:e103438. 10.1371/journal.pone.0103438

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 361

  PerluigiM.CocciaR.ButterfieldD. A. (2012). 4-Hydroxy-2-Nonenal, a reactive product of lipid peroxidation, and neurodegenerative diseases: a toxic combination illuminated by redox proteomics studies.Antioxid. Redox Signal.171590–1609. 10.1089/ars.2011.4406

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 362

  PetersO. M.GhasemiM.BrownR. H. (2015). Emerging mechanisms of molecular pathology in ALS.J. Clin. Invest.1251767–1779. 10.1172/JCI71601

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 363

  PetrovD.MansfieldC.MoussyA.HermineO. (2017). ALS clinical trials review: 20 years of failure. Are we any closer to registering a new treatment?Front. Aging Neurosci.9:68. 10.3389/fnagi.2017.00068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 364

  PetrozziL.RicciG.GiglioliN. J.SicialianoG.MancusoM. (2007). Mitochondria and neurodegeneration.Biosci. Rep.2787–104. 10.1007/s10540-007-9038-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 365

  PfohlS. R.HalicekM. T.MitchellC. S. (2015). Characterization of the contribution of genetic brackground and gender to disease progression in the SOD1 G93A mouse model of amyotrophic lateral sclerosis: a meta-analysis.J. Neuromuscul. Dis.2137–150. 10.3233/JND-140068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 366

  PhaniendraA.JestadiD. B.PeriyasamyL. (2015). Free radicals: properties, sources, targets, and their implication in various diseases.Indian J. Clin. Biochem.3011–26. 10.1007/s12291-014-0446-0

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 367

  PicklesS.DestroismaisonsL.PeyrardS. L.CadotS.RouleauG. A.BrownR. H.et al (2013). Mitochondrial damage revealed by immunoselection for ALS-linked misfolded SOD1.Hum. Mol. Genet.223947–3959. 10.1093/hmg/ddt249

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 368

  PicklesS.SemmlerH. R.BroomL.DestroismaisonsL.LegrouxN.ArbourE.et al (2016). ALS-linked misfolded SOD1 species have divergent impacts on mitocondria.Acta Neuropathol. Commun.4:43. 10.1186/s40478-016-0313-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 369

  PizzinoG.IrreraN.CucinottaM.PallioG.ManninoF.ArcoraciV.et al (2017). Oxidative stress: harms and benefics for human health.Oxid. Med. Cell. Longev.2017:8416763. 10.1155/2017/8416763

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 370

  PolimeniG.EspositoE.BevelacquaV.GuarneriC.CuzzocreaS. (2014). Role of melatonin supplementation in neurodegenerative disorders.Front. Biosci.19429–446. 10.2741/4217

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 371

  PoljsakB.MilisavI. (2016). NAD+ as the link between oxidative stress, inflammation, caloric restriction, exercise, DNA repair, longevity, and health span.Rejuvenation Res.19406–413. 10.1089/rej.2015.1767

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 372

  PollariE.GoldsteinsG.BartG.KoistinahoJ.GiniatullinR. (2014). The role of oxidative stress in degeneration of the neuromuscular junction in amyotrophic lateral sclerosis.Front. Cell. Neurosci.8:131. 10.3389/fncel.2014.00131

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 373

  Popa-WagnerA.MitranS.SivanesanS.ChangE.BugaA. M. (2013). ROS and brain diseases: the good, the bad and the ugly.Oxid. Med. Cell. Longev.2013:963520. 10.1155/2013/963520

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 374

  PorquetD.CasadesusC.BayodS.VicenteA.CanudasA. M.VilaplanaJ.et al (2013). Dietary resveratrol prevents Alzheimer’s markers and increases life span in SAMP8.Age351851–1865. 10.1007/s11357-012-9489-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 375

  PouloseS. M.MillerM. G.Shukitt-HaleB. (2014). Role of walnuts in maintaining brain health with age.J. Nutr.144(4 Suppl.), 561S–566S. 10.3945/jn.113.184838

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 376

  PouloseS. M.ThanthaengN.MillerM. G.Shukitt-HaleB. (2015). Effects of pterostilbene and resveratrol on brain and behaviour.Neurochem. Int.89227–233. 10.1016/j.neuint.2015.07.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 377

  ProuskyJ.MillmanC. G.KiklandJ. B. (2011). Pharmacologic use of niacin.J. Evid. Based Intedr. Med.1691–101. 10.1177/2156587211399579

  • CrossRef
  • Google Scholar

• 378

  PrzedborskiS.DonaldsonD. M.MurphyP. L.HirschO.LangeD.NainiA. B.et al (1996). Blood superoxide dismutase, catalase and glutathione peroxidase activities in familial and sporadic amyotrophic lateral sclerosis.Neurodegeneration557–64.

  • Pubmed Abstract
  • Google Scholar

• 379

  QiuX.BrownK.HirscheyM. D.VerdinE.ChenD. (2010). Calorie restriction reduces oxidative stress by SIRT3-mediated SOD2 activation.Cell Metab.12662–667. 10.1016/j.cmet.2010.11.015

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 380

  QuinW.HaroutunianV.KatselP.CardozoC. P.HoL.BuxbaumJ. D.et al (2009). PGC-1 alpha expression decreases in the Alzheimer diasease brain as a function of dementia.Arch. Neurol.66352–361. 10.1001/archneurol.2008.588

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 381

  RadakZ.ZhaoZ.GotoS.KoltaiE. (2011). Age-associated neurodegeneration and oxidative damage to lipids, proteins and DNA.Mol. Aspects Med.32305–315. 10.1016/j.mam.2011.10.010

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 382

  RaffM. C.WhitmoreA. V.FinnJ. T. (2002). Axonal self-destruction and neurodegeneration.Science296868–871. 10.1126/science.1068613

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 383

  RajmanL.ChwalekK.SinclairD. A. (2018). Therapeutic potential of NAD-boosting molecules: the in vivo evidence.Cell Metab.27529–547. 10.1016/j.cmet.2018.02.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 384

  RakotoarisoaM.AngelovaA. (2018). Amphiphilic nanocarrier systems for curcumin delivery in neurodegenerative disorders.Medicines5:E126. 10.3390/medicines5040126

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 385

  RamamoorthyM.SykoraP.Scheibye-KnudsenM.DunnC.KasmerC.ZhangY.et al (2012). Sporadic Alzheimer disease fibroblasts display an oxidative stress pehnotype.Free Radic. Biol. Med.531371–1380. 10.1016/j.freeradbiomed.2012.07.018

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 386

  RaskinJ.CummingsJ.HardyJ.SchuhK.DeanR. A. (2015). Neurobiology of Alzheimer’s Disease: integrated molecular, physiological, anatomical, biomarker, and cognitive dimensions.Curr. Alzheimer Res.12712–722.

  • Google Scholar

• 387

  RassU.AhelI.WestS. C. (2007). Defective DNA repair and neurodegenerative disease.Cell130991–1004. 10.1016/j.cell.2007.08.043

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 388

  RayP. D.HuangB. W.TsujiY. (2012). Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling.Cell Signal.24981–990. 10.1016/j.cellsig.2012.01.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 389

  RechtmannL.WagnerL.KayeW.VillanacciJ. (2015). Update prevalence and demographic characteristics for ALS cases in Texas, 2009-2011.South. Med. J.108483–486. 10.14423/SMJ.0000000000000324

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 390

  RegueiroJ.Sánchez-GonzálezC.Vallverdú-QueraltA.Simal-GándaraJ.Lamuela-RaventósR.Izquierdo-PulidoM. (2014). Comprehensive identification of walnut polyphenols by liquid chromatography coupled to linear ion trap– Orbitrap mass spectrometry.Food Chem.152340–348. 10.1016/j.foodchem.2013.11.158

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 391

  ReinisaloM.KarlundA.KoskelaA.KaarnirantaK.KarjalainenR. O. (2015). Polyphenol stilbenes: molecular mechanisms of defence against oxidative stress and aging-related diseases.Oxid. Med. Cell. Longev.2015:340520. 10.1155/2015/340520

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 392

  RemsbergC. M.YáñezJ. A.OhgamiY.Vega-VillaK. R.RimandoA. M.DaviesN. M. (2008). Pharmacometrics of pterostilbene: preclinical pharmacokinetics and metabolism, anticancer, antiinflammatory, antioxidant and analgesic activity.Phytother. Res.22169–179. 10.1002/ptr.2277

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 393

  RenaudJ.MartinoliM. G. (2019). Consideration for the use of polyphenols as therapies in neurodegenerative diseases.Int. J. Mol. Sci.20:E1883. 10.3390/ijms20081883

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 394

  RheeS. G.ChangT. S.BaeY. S.LeeS. R.KangS. W. (2003). Cellular regulation by hydrogen peroxide.J. Am. Soc. Nephrol.14(8 Suppl. 3), S211–S215. 10.1097/01.asn.0000077404.45564.7e

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 395

  RichardsonK.AllenS. P.MortiboysH.GriersonA. J.WhartonS. B.InceP. G.et al (2013). The effect of SOD1 mutation on cellular bioenergetics profile and viability in response to oxidative stress and influence of mutation-type.PLoS One8:e68256. 10.1371/journal.pone.0068256

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 396

  RicheD. M.McEwenC. L.RicheK. D.ShermanJ. J.WoffordM. R.DeschampD.et al (2013). Analysis of safety from a human clinical trial with pterostilbene.J. Toxicol.2013:463595. 10.1155/2013/463595

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 397

  RimandoA. M.CuendetM.DesmarchelierC.MehtaR. G.PezzutoJ. M.DukoS. O. (2002). Cancer chemopreventive and antioxidant activities of pterostilbene, a naturally ocurring analogue of resveratrol.J. Agric. Food Chem.503453–3457.

  • Google Scholar

• 398

  RivièreC.PawlusA. D.MérillonJ. M. (2012). Natural stilbenoids: distribution in the plant kingdom and chemotaxonomic interest in vitaceae.Nat. Prod. Rep.291317–1333. 10.1039/c2np20049j

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 399

  RobberechtW. (2000). Oxidative stress in amyotrophic lateral sclerosis.J. Neurol.247(Suppl. 1), 1–6.

  • Google Scholar

• 400

  RodgersJ. T.LerinC.HaasW.GygiS. P.SpiegelmanB. M.PuigserverP. (2005). Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1.Nature434113–118. 10.1038/nature03354

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 401

  RogersN. M.SeegerF.GarcinE. D.RobertsD. D.IsenbergJ. S. (2014). Regulation of soluble guanylate cyclase by matricellular thrombospondins: implications for blood flow.Front. Physiol.5:134. 10.3389/fphys.2014.00134

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 402

  RojasF.GonzálezD.CortesN.AmpueroE.HernándezD. E.FritzE.et al (2015). Reactive oxygen species trigger motoneuron death in non-cell-autonmous models of ALS through activation of c-Abl signaling.Front. Cell. Neurosci.9:203. 10.3389/fncel.2015.00203

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 403

  RomanoA. D.ServiddioG.de MatthaeisA.BellantiF.VendemialeG. (2010). Oxidative stress and aging.J. Nephrol.23(Suppl. 15):36.

  • Pubmed Abstract
  • Google Scholar

• 404

  RonnettG. B.RamamurthyS.KlemanA. M.LandreeL. E.AjaS. (2009). AMPK in the brain: its roles in energy balance and neuroprotection.J. Neurochem.10917–23. 10.1111/j.1471-4159.2009.05916.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 405

  RossiM.CarusoF.AntoniolettiR.VigliantiA.TraversiG.LeoneS.et al (2013). Scavenging of hydroxyl radical by resveratrol and related natural stilbenes after hydrogen peroxide attack on DNA.Chem. Biol. Interact.206175–185. 10.1016/j.cbi.2013.09.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 406

  RothsteinJ. D. (2017). Edaravone: a new drug approved for ALS.Cell171:725. 10.1016/j.cell.2017.10.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 407

  RübU.StratmannK.HeinsenH.SeidelK.BouzrouM.KorfH. W. (2017). Alzheimer’s disease: characterization of the brain sites of the initial tau cytoskeletal pathology will improve the success of novel immunological anti-tau treatment approaches.J. Alzheimers Dis.57683–696. 10.3233/JAD-161102

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 408

  RuizM. J.FernándezM.PicóY.MañesJ.AsensiM.CardaC.et al (2009). Dietary administration of high doses of pterostilbene and quercetin to mice is not toxic.J. Agric. Food Chem.573180–3186. 10.1021/jf803579e

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 409

  RusconiM.ContiA. (2010). Theobroma cacao L., the food of the gods: a scientific approach beyond myths and claims.Pharmacol. Res.615–13. 10.1016/j.phrs.2009.08.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 410

  RyuD.ZhangH.RopelleE. R.SorrentinoV.MázalaD. A.MouchiroudL.et al (2016). NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation.Sci. Transl. Med.8:361ra139. 10.1126/scitranslmed.aaf5504

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 411

  RzheshevskyA. V. (2014). Decrease in ATP biosynthesis and dysfunction of biological membranes. Two possible key mechanisms of phenoptosis.Biochemistry791056–1068. 10.1134/S0006297914100071

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 412

  SacconR. A.Bunton-StasyshynR. K.FisherE. M.FrattaP. (2013). Is SOD1 loss of function involved in amyotrophic lateral sclerosis?Brain136(Pt 8), 2342–2358. 10.1093/brain/awt097

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 413

  SalisburyD.BronasU. (2015). Reactive oxygen and nitrogen species: impact on endothelial dysfunction.Nurs. Res.6453–66. 10.1097/NNR.0000000000000068

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 414

  SalvatoriI.ValleC.FerriA.CarrìM. T. (2017). SIRT3 and mitochondrial metabolism in neurodegenerative diseases.Neurochem. Int.109184–192. 10.1016/j.neuint.2017.04.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 415

  Santa-CruzL. D.TapiaR. (2014). Role of energy metabolic déficits and oxidative stress in extcitotoxic spinal motor neuron degeneration in vivo.ANS Neuro6:e00138. 10.1042/AN20130046

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 416

  SarasijaS.NormanK. R. (2018). Role of presenilin in mitochondrial oxidative stress and neurodegeneration in Caenorhabditis elegans.Antioxidants7:111. 10.3390/antiox7090111

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 417

  SasakiS.ShibataN.KomoriT.IwataT. (2000). iNOS and nitrotyrosine immunoreactivity in amyotrophic lateral sclerosis.Neurosci. Lett.29144–48.

  • Pubmed Abstract
  • Google Scholar

• 418

  SasakiY.ArakiT.MildbrandtJ. (2006). Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy.J. Neurosci.268484–8491. 10.1523/JNEUROSCI.2320-06.2006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 419

  SawC. L.GuoY.YangA. Y.Paredes-GonzalezX.RamirezC.PungD.et al (2014). The berry constituents quercetin, kaempferol and pterostilbene synergistically attenuate reactive oxygen species: involvement of the Nrf2-ARE signaling pathway.Food Chem. Toxicol.72303–311. 10.1016/j.fct.2014.07.038

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 420

  SawadaH. (2017). Clinical efficacy of edaravone for the treatment of amyotrophic lateral sclerosis.Expert Opin. Pharmacother.18735–738. 10.1080/14656566.2017.1319937

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 421

  SchettersS. T. T.Gómez-NicolaD.García-VallejoJ. J.Van KooykY. (2018). Neuroinflammation: microglia and T Cells Get ready to tango.Front. Immunol.8:1905. 10.3389/fimmu.2017.01905

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 422

  SchieberM.ChandelN. S. (2014). ROS function in redox signaling and oxidative stress.Curr. Biol.24R453–R462. 10.1016/j.cub.2014.03.034

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 423

  SchmidtM.BrennerC. (2019). Absence of evidence that Slc12a8 encodes a nicotinamide mononucleotide transporter.Nat. Metab.1660–661. 10.1038/s42255-018-0009-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 424

  SchonE. A.ManfrediG. (2003). Neuronal degeneration and mitochondrial dysfunction.J. Clin. Invest.111303–312. 10.1172/JCI200317741

  • CrossRef
  • Google Scholar

• 425

  SchöndorfD. C.IvanyukD.BadenP.Sánchez-MartínezA.De CircoS.YuC.et al (2018). The NAD+ precursor nicotinamide riboside rescues mitochondrial defects and neuronal loss in iPSC and fly models of Parkinson’s disease.Cell Rep.232976–2988. 10.1016/j.celrep.2018.05.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 426

  ScialòF.Fernández-AyalaD. J.SanzA. (2017). Role of mitochondrial reverse electron transport in ROS signaling: potential roles in health and disease.Front. Physiol.27:428. 10.3389/fphys.2017.00428

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 427

  SelvarajiS.PohL.NatarajanV.MallilankaramanK.ArumuganT. V. (2019). Negative conditioning of mitochondrial dysfunction in age-related neurodegenerative diseases.Cond. Med.230–39.

  • Pubmed Abstract
  • Google Scholar

• 428

  SeoE. J.FischerN.EfferthT. (2018). Phytochemicals as inhibitors of NF-kB for treatment of Alzheimer’s disease.Pharmacol. Res.129262–273. 10.1016/j.phrs.2017.11.030

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 429

  Sferrazza-PapaG. F.PellegrinoG. M.ShaikhH.LaxA.LoriniL.CorboM. (2018). Respiratory muscle testing in amyotrophic lateral sclerosis: a practical approach.Minerva Med.109(6 Suppl. 1), 11–19. 10.23736/S0026-4806.18.05920-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 430

  SharinaI. G.MartinE. (2017). The role of reactive oxygen and nitrogen species in the expression and splicing of nitric oxide receptor.Antioxid. Redox Signal.26122–136. 10.1089/ars.2016.6687

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 431

  SharmaD. R.WaniW. Y.SunkariaA.KandimallaR. J.SharmaR. K.VermaD.et al (2016). Quercetin attenuates neuronal death against aluminium-induced neurodegeneration in the rat hippocampus.Neuroscience324163–176. 10.1016/j.neuroscience.2016.02.055

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 432

  ShenY.Aoyagi-ScharberM.WangB. (2015). Trapping poly(ADP-Ribose) polymerase.J. Pharmacol. Exp. Ther.353446–457. 10.1124/jpet.114.222448

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 433

  ShibataN.HiranoA.Hedley-WhyteE. T.Dal CantoM. C.NagaiR.UchidaK.et al (2002). Selective formation of certain advanced glycation end products in spinal cord astrocytes of humans and mice with superoxide dismutase-1 mutation.Acta Neuropathol.104171–178. 10.1007/s00401-002-0537-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 434

  ShinJ. A.LeeH.LimY. K.KohY.ChoiJ. H.ParkE. M. (2010). Therapeutic effects of resveratrol during acute periods following experimental ischemic stroke.J. Neuroimmunol.22793–100. 10.1016/j.jneuroim.2010.06.017

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 435

  SidranskyE.NallsM. A.AaslyJ. O.Aharon-PeretzJ.AnnesiG.BarbosaE. R.et al (2009). Multicenter analysis of glucocerebroside mutations in Parkison’s disease.N. Engl. J. Med.3611651–1661. 10.1056/NEJMoa0901281

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 436

  SiesH. (1986). Biochemistry of oxidative stress.Angew. Chem. Int. Ed. Engl.251058–1071. 10.1002/anie.198610581

  • CrossRef
  • Google Scholar

• 437

  SimpkinsJ. W.DykensJ. A. (2008). Mitochondrial mechanisms of estrogen neuroprotection.Brain Res. Rev.57421–430. 10.1016/j.brainresrev.2007.04.007

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 438

  SimpsonE. P.HenryY. K.HenkelJ. S.SmithR. G.AppelS. H. (2004). Increased lipid peroxidation in será of ALS patients: a potential biomarker of disease burden.Neurology621758–1765.

  • Google Scholar

• 439

  SinghS. P.SchragenheimJ.CaoJ.FalckJ. R.AbrahamN. G.BellnerL. (2016). PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: role of epoxyeicosatrienoic acid.Prostaglandins Other Lipid Mediat.1258–18. 10.1016/j.prostaglandins.2016.07.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 440

  SirerolJ. A.RodríguezM. L.MenaS.AsensiM. A.EstrelaJ. M.OrtegaA. L. (2016). Role of natural stilbenes in the prevention of cancer.Oxid. Med. Cell. Longev.2016:3128951. 10.1155/2016/3128951

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 441

  SmithE. F.ShawP. J.De VosK. J. (2017). The role of mitochondria in Amyotrophic Lateral Sclerosis.Neurosci. Lett.710:132933. 10.1016/j.neulet.2017.06.052

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 442

  SohmiyaM.TanakaM.SusukiY.TaninoY.OkamotoK.YamamotoY. (2005). An increase of oxidized coenzyme Q-10 occurs in the plasma of sporadic ALS patients.J. Neurol. Sci.22849–53. 10.1016/j.jns.2004.09.030

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 443

  SolankiI.PariharP.MansuriM. L.PariharM. S. (2015). Flavonoid-based therapies in the early management of neurodegenerative diseases.Adv. Nutr.664–72. 10.3945/an.114.007500

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 444

  Solleiro-VillavicencioH.Rivas-ArancibiaS. (2018). Effect of chronic oxidative stress on neuroinflammatory response mediated by CD4+T cells in neurodegenerative diseases.Front. Cell. Neurosci.12:114. 10.3389/fncel.2018.00114

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 445

  SongL.ChenL.ZhangX.LiJ.LeW. (2014). Resveratrol ameliorates motor neuron degeneration and improves survival in SOD1(G93A) mouse model of amyotrophic lateral sclerosis.Biomed. Res. Int.2014:483501. 10.1155/2014/483501

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 446

  SongZ.HanS.PanX.GongY.WangM. (2015). Pterostilbene mediates neuroprotection against oxidative toxicity via oestrogen receptor α signalling pathways.J. Pharm. Pharmacol.67720–730. 10.1111/jphp.12360

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 447

  SrinivasanE.RajasekaranR. (2018). Quantum chemical and molecular mechanisms studies on the assessment of interactions between resveratrol and mutant SOD1 (G93A) protein.J. Comput. Aided Mol. Des.321347–1361. 10.1007/s10822-018-0175-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 448

  SrivastavaS. (2016). Emerging therapeutic roles for NAD(+) metabolism in mitochondrial and age-related disorders.Clin. Transl. Med.5:25. 10.1186/s40169-016-0104-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 449

  StaiculescuM. C.FooteC.MeiningerG. A.Martínez-LemusL. A. (2014). The role of reactive oxygen species in microvascular remodeling.Int. J. Mol. Sci.1523792–23835. 10.3390/ijms151223792

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 450

  St-PierreJ.DroriS.UldryM.SilvaggiJ. M.RheeJ.JägerS.et al (2006). Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional activators.Cell127397–408. 10.1016/j.cell.2006.09.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 451

  StrongM. J.PatteeG. L. (2000). Creatine and coenzyme Q10 in the treatment of ALS.Amyotroph. Lateral Scler. Other Motor Neuron Disord.417–20.

  • Google Scholar

• 452

  SwinnenB.RobberechtW. (2014). The phenotypic variability of amyotrophic lateral sclerosis.Nat. Rev. Neurol.10661–670. 10.1038/nrneurol.2014.184

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 453

  SzkudelskiT.SzkudelskaK. (2015). Resveratrol and diabetes: from animal to human studies.Biochim. Biophys. Acta18521145–1154. 10.1016/j.bbadis.2014.10.013

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 454

  SzwajgierD.BorowiecK.PustelniakK. (2017). The neuroprotective effects of phenolic acids: molecular mechanism of action.Nutrients9:E477. 10.3390/nu9050477

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 455

  TalbotK. (2016). Clinical tool for predicting survival in ALS: do we need one?J. Neurol. Neurosurg. Psychiatry87:1275. 10.1136/jnnp-2016-313683

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 456

  TalhaouiN.Gómez-CaravacaA. M.LeónL.De la RosaR.Fernández-GutiérrezA.Segura-CarreteroA. (2016). From olive fruits to olive oil: phenolic compound transfer in six different olive cultivars grown under the same agronomical conditions.Int. J. Mol. Sci.17:337. 10.3390/ijms17030337

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 457

  TanB. L.NorhaizanM. E.LiewW. P.Sulaiman-RahmanH. (2018). Antioxidant and oxidative stress: a mutual interplay in age-related diseases.Front. Pharmacol.9:1162. 10.3389/fphar.2018.01162

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 458

  TanW.PasinelliP.TrottiD. (2014). Role of mitochondria in mutant SOD1 linked amyotrophic lateral sclerosis.Biochim. Biophys. Acta18421295–1301. 10.1016/j.bbadis.2014.02.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 459

  TangB. L. (2016). Sirt1 and the mitochondria.Mol. Cells3987–95. 10.14348/molcells.2016.2318

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 460

  TangB. L. (2017). Could sirtuins activities modify ALS onset and progression?Cell. Mol. Neurobiol.371147–1160. 10.1007/s10571-016-0452-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 461

  TariqueH.TanB.YulongY.BlachierF.MyrleneC. B.NajmaR. (2016). Oxidative stress and inflammation: what polyphenols can do for us?Oxid. Med. Cell. Longev.2016:7432797. 10.1155/2016/7432797

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 462

  TemsamaniH. K. S.MerillonJ. M.RichardT. (2015). Promising neuroprotective effects of oligostilbenes.Nutr. Aging349–54. 10.3233/NUA-150050

  • CrossRef
  • Google Scholar

• 463

  TennenR. I.ChuaK. F. (2011). Chromatin regulation and genome maintenance by mammalian SIRT6.Trends Biochem. Sci.3639–46. 10.1016/j.tibs.2010.07.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 464

  TeraoJ.PiskulaM.YaoQ. (1994). Protective effect of epicatechin, epicatechin gallate, and quercetin on lipid peroxidation in phospholipid bilayers.Arch. Biochem. Biophys.308278–284. 10.1006/abbi.1994.1039

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 465

  ThandapillyS. J.LouisX. L.YangT.StringerD. M.YuL.ZhangS.et al (2011). Resveratrol prevents norepinephrine induced hypertrophy in adult rat cardiomyocytes, by activating no-ampk pathway.Eur. J. Pharmacol.668217–222. 10.1016/j.ejphar.2011.06.042

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 466

  ThibaultO.GantJ. C.LandfieldP. W. (2007). Expansion of the calcium hypothesis of braing aging and Alzheimer’s disease: minding the store.Aging Cell6307–317. 10.1111/j.1474-9726.2007.00295.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 467

  ThirupathiA.de SouzaC. T. (2017). Multi-regulatory network of ROS: the interconnection of ROS, PGC-1 alpha, and AMPK-SIRT1 during exercise.J. Physiol. Biochem.73487–494. 10.1007/s13105-017-0576-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 468

  TrammellS. A.SchmidtM. S.WeidemannB. J.RedpathP.JakschF.DelingerR. W.et al (2016). Nicotinamide riboside is uniquely and orally bioavaliable in mice and humans.Nat. Commun.7:12948. 10.1038/ncomms12948

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 469

  TraversiG.FioreM.LeoneS.BassoE.Di MuzioE.PolticelliF.et al (2016). Resveratrol and its methoxy-derivatives as modulators of DNA damage induced by ionizing radiation.Mutagenesis31433–441. 10.1093/mutage/gew002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 470

  Tressera-RimbauA.ArranzS.EderM.Vallverdú-QueraltA. (2017). Dietary polyphenols in the prevention of stroke.Oxid. Med. Cell. Longev.2017:7467962. 10.1155/2017/7467962

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 471

  TripodoG.ChlapanidasT.PerteghellaS.ViganiB.MandracchiaD.TrapaniA.et al (2015). Mesenchymal stromal cells loading curcumin-INVITE-micelles: a drug delivery system for neurodegenerative diseases.Colloids Surf. B Biointerfaces125300–308. 10.1016/j.colsurfb.2014.11.034

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 472

  TurnerM. R.BowserR.BruijinL.DupuisL.LudolphA.McgrathM.et al (2013). Mechanisms, models and biomarkers in amyotrophic lateral sclerosis.Amyotroph. Lateral Scler. Frontotemporal. Degener.14(Suppl. 1), 19–32. 10.3109/21678421.2013.778554

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 473

  TurrensJ. F. (2003). Mitochondrial formation of reactive oxygen species.J. Physiol.552(Pt 2), 335–344. 10.1113/jphysiol.2003.049478

  • CrossRef
  • Google Scholar

• 474

  UllahF.LiangA.RangelA.GyengesiE.NiedermayerG.MünchG. (2017). High bioavailability curcumin: an anti-inflammatory and neurosupportive bioactive nutrient for neurodegenerative diseases characterized by chronic neuroinflammation.Arch. Toxicol.911623–1634. 10.1007/s00204-017-1939-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 475

  ValkoK.CieslaL. (2019). Amyotrophic lateral sclerosis.Prog. Med. Chem.5863–117. 10.1016/bs.pmch.2018.12.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 476

  ValkoM.LeibfritzD.MoncolJ.CroninM. T.MazurM.TelserJ. (2007). Free radicals and antioxidants in normal physiological functions and human disease.Int. J. Biochem. Cell Biol.3944–84. 10.1016/j.biocel.2006.07.001

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 477

  ValleC.CarrìM. T. (2017). Cysteine modifications in the pathogenesis of ALS.Front. Mol. Neurosci.10:5. 10.3389/fnmol.2017.00005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 478

  Vallverdú-QueraltA.BoixN.PiquéE.Gómez-CatalánJ.Medina-RemonA.SasotG.et al (2015). Identification of phenolic compounds in red wine extract samples and zebrafisch embryos by HPLC-ESI-LTQ-Orbitrap-MS.Food Chem.181146–151. 10.1016/j.foodchem.2015.02.098

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 479

  Vallverdú-QueraltA.RegueiroJ.Martínez-HuélamoM.Rinaldi-AlvarengaJ. F.LealL. N.Lamuela-RaventosR. M. (2014). A comprehensive study on the phenolic profile of widely used culinary herbs and spices: rosemary, thyme, oregano, cinnamon, cumin and bay.Food Chem.154299–307. 10.1016/j.foodchem.2013.12.106

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 480

  Van DammeP.RobberechtW.Van Den BoschL. (2017). Modelling amyotrophic lateral sclerosis: progress and possibilities.Dis. Model. Mech.10537–549. 10.1242/dmm.029058

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 481

  Van EsM. A.HardimanO.ChioA.Al-ChalabiA.PasterkampR. J.VeldinkJ. H.et al (2017). Amyotrophic lateral sclerosis.Lancet3902084–2098. 10.1016/S0140-6736(17)31287-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 482

  Van GiauV.AnS. S. A.HulmeS. P. (2018). Mitochondrial therapeutic interventions in Alzheimer’s disease.J. Neurol. Sci.39562–70. 10.1016/j.jns.2018.09.033

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 483

  Van HorssenJ.Van SchaikP.WitteM. (2017). Inflammation and mitochondrial dysfunction: a vicious circle in neurodegenerative disorders?Neurosci. Lett.710:132931. 10.1016/j.neulet.2017.06.050

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 484

  Van HorssenJ.WitteM. E.SchreibeltG.De VriesH. E. (2011). Radical changes in multiple sclerosis pathogenesis.Biochim. Biophys. Acta1812141–150. 10.1016/j.bbadis.2010.06.011

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 485

  Van HoutenB.WoshnerV.SantosJ. H. (2006). Role of mitochondrial DNA in toxic responses to oxidative stress.DNA Repair5145–152. 10.1016/j.dnarep.2005.03.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 486

  Van’t ErveT. J.KadiiskaM. B.LondonS. J.MasonR. P. (2017). Classifying oxidative stress by F2-isoprostane levels across human diseases: a meta-analysis.Redox Biol.12582–599. 10.1016/j.redox.2017.03.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 487

  VaurP.BruggB.MericskayM.LiZ.SchmidtM. S.VivienD.et al (2017). Nicotinamide riboside, a form of vitamin B3, protects againts excitotoxicity-induced axonal degeneration.FASEB J.315440–5452. 10.1096/fj.201700221RR

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 488

  VauzourD.VafeiadouK.Rodriguez-MateosA.RendeiroC.SpencerJ. P. E. (2008). The neuroprotective potential of flavonoids: a multiplicity of effects.Genes Nutr.3115–126. 10.1007/s12263-008-0091-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 489

  VeldinkJ. H.KalmijnS.GroeneveldG. J.WunderinkW.KosterA.de VriesJ. H. M.et al (2007). Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis.J. Neurol. Neurosurg. Psychiatr.78367–371. 10.1136/jnnp.2005.083378

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 490

  VendittiP.Di StefanoL.Di MeoS. (2013). Mitochondrial metabolism of reactive oxygen species.Mitochondrion1371–82. 10.1016/j.mito.2013.01.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 491

  VerdinE. (2015). NAD+ in aging, metabolism, and neurodegeneration.Science3501208–1213. 10.1126/science.aac4854

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 492

  VijayvergiyaC.BealM. F.BuckJ.ManfrediG. (2005). Mutant superoxide dismutase 1 forms aggregates in the brain mitochondrial matrix of amyotrophic lateral sclerosis mice.J. Neurosci.252463–2470. 10.1523/JNEUROSCI.4385-04.2005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 493

  VoloshynaI.HaiO.LittlefieldM. J.CarsonsS.ReissA. B. (2013). Resveratrol mediates anti-atherogenic effects on cholesterol flux in human macrophages and endothelium via pparγ and adenosine.Eur. J. Pharmacol.698299–309. 10.1016/j.ejphar.2012.08.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 494

  WangB.LiuH.YueL.LiX.ZhaoL.YangX.et al (2016). Neuroprotective effects of pterostilbene against oxidative stress injury: involvement of nuclear factor erythroid 2-related factor 2 pathway.Brain Res.164370–79. 10.1016/j.brainres.2016.04.048

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 495

  WangH.O’reillyE. J.WeisskopfM. G.LogroscinoG.McCulloughM. L.SchatzkinA.et al (2011). Vitamin E intake and risk of amyotrophic lateral sclerosis: a pooled analysis of data from 5 prospective cohort studies.Am. J. Epidemiol.173595–602. 10.1093/aje/kwq416

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 496

  WangJ.ZhaiQ.ChenY.LinE.GuW.McBurneyM. W.et al (2005). A local mechanism mediates NAD-dependent protection of axon degeneration.J. Cell Biol.170349–355. 10.1083/jcb.200504028

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 497

  WangJ.ZhangY.TangL.ZhanN.FanD. (2011). Protective effects of resveratrol through the up-regulation of SIRT1 expression in the mutant hSOD1-G93A-bearing motor neuron-like cell culture model of amyotrophic lateral sclerosis.Neurosci. Lett.503250–255. 10.1016/j.neulet.2011.08.047

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 498

  WangQ.LiL.LiC. Y.PeiZ.ZhouM.LiN. (2015). SIRT3 protects cells from hypoxia via PGC-1α- and MnSOD-dependent pathways.Neuroscience12109–121. 10.1016/j.neuroscience.2014.11.045

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 499

  WangT. H.WangS. Y.WangX. D.JiangH. Q.YangY. Q.WangY.et al (2018). Fisetin exerts antioxidant and neuroprotective effects in multiple mutant hSOD1 models of amyotrophic lateral sclerosis by activating ERK.Neuroscience379152–166. 10.1016/j.neuroscience.2018.03.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 500

  WangY.XuE.MusichP. R.LinF. (2019). Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure.CNS Neurosci. Ther.25816–824. 10.1111/cns.13116

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 501

  WatanabeK.TanakaM.YukiS.HirajM.YamamotoY. (2018). How is edaravone effective against acute ischemic stroke and amyotrophic lateral sclerosis?J. Clin. Biochem. Nutr.6220–38. 10.3164/jcbn.17-62

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 502

  WeiQ.ChenX.ChenY.OuR.CaoB.HouY.et al (2019). Unique characteristics of the genetics epidemiology of amyotrophic lateral sclerosis in China.Sci. China Life Sci.62517–525. 10.1007/s11427-018-9453-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 503

  WeiduschatN.MaoX.HupfJ.ArmstrongN.KangG.LangeD. J.et al (2014). Motor cortex glutathione déficit in ALS measured in vivo with the J-editing technique.Neurosci. Lett.570102–107. 10.1016/j.neulet.2014.04.020

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 504

  WeishauptJ. H.BartelsC.PölkingE.DietrichJ.RohdeG.PoeggelerB.et al (2006). Reduced oxidative damage in ALS by high-dose enteral melatonin treatment.J. Pineal. Res.41313–323. 10.1111/j.1600-079X.2006.00377.x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 505

  WierC. G.CrumA. E.ReynoldsA. B.IyerC. C.ChughD.PalettasM. S.et al (2019). Muscle contractility dysfunction precedes loss of motor unit connectivity in SOD1(G93A) mide.Muscle Nerve59254–262. 10.1002/mus.26365

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 506

  WitteM. E.GeurtsJ. J.de VriesH. E.Van der ValkP.Van HorssenJ. (2010). Mitochondrial dysfunction: a pontential link between neuroinflammation and neurodegeneration?Mitochondrion10411–418. 10.1016/j.mito.2010.05.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 507

  WuZ.HuangX.FengY.HandschinC.FengY.GullicksenP. S.et al (2006). Transducer of regulated CREB-binding proteins (TORCs) induce PGC-1alpha transcription and mitochondrial biogénesis in muscle cells.Proc. Natl. Acad. Sci. U.S.A.10314379–14384. 10.1073/pnas.0606714103

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 508

  XiaoY.KaramC.YiJ.ZhangL.LiX.YoonD.et al (2018). ROS-related mitochondrial dysfunction in skeletal muscle of an ALS mouse model during the disease progression.Pharmacol. Res.13825–36. 10.1016/j.phrs.2018.09.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 509

  XieY.ChenJ.XiaoA.LiuL. (2017). Antibacterial activity of polyphenols: structure-activity relationship and influence of hyperglycemic condition.Molecules22:1913. 10.3390/molecules22111913

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 510

  XuZ.ChenS.LiX.LuoG.LiL.LeW. (2006). Neuroprotective effects of (-)-epigallocatechin-3-gallate in a transgenic mouse model of amyotrophic lateral sclerosis.Neurochem. Res.311263–1269. 10.1007/s11064-006-9166-z

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 511

  XueE. X.LinJ. P.ZhangY.ShengS. R.LiuH. X.ZhouY. L.et al (2017). Pterostilbene inhibits inflammation and ROS production in chondrocytes by activating Nrf2 pathway.Oncotarget841988–42000. 10.18632/oncotarget.16716

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 512

  YakuK.OkabeK.NakagawaT. (2018). NAD metabolism: implications in aging and longevity.Ageing Res. Rev.471–17. 10.1016/j.arr.2018.05.006

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 513

  YamamotoY. (2016). Coenzyme Q10 redox balance and a free radical scavenger drug.Arch. Biochem. Biophys.595132–135. 10.1016/j.abb.2015.11.026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 514

  YangH.YangT.BaurJ. A.PérezE.MatsuiT.CarmonaJ. J.et al (2007). Nutrient-sensitive mitochondrial NAD+ levels dictate cell survival.Cell1301095–1107. 10.1016/j.cell.2007.07.035

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 515

  YangT.ChanN. Y.SauveA. A. (2007). Synthesis of nicotinamide riboside and derivatives: effective agents for increasing nicotinamide adenine dinucleotide concentrations in mammalian cells.J. Med. Chem.506458–6461. 10.1021/jm701001c

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 516

  YangY.FanC.WangB.MaZ.WangD.GongB.et al (2017). Pterostilbene attenuates high glucose-induced oxidative injury in hippocampal neuronal cells by activating nuclear factor erythroid 2-related factor 2.Biochim. Biophys. Acta. Mol. Basis Dis.1863827–837. 10.1016/j.bbadis.2017.01.005

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 517

  YangY.SauveA. A. (2016). NAD(+) metabolism: bioenergetics, signaling and manipulation for therapy.Biochim. Biophys. Acta18641787–1800. 10.1016/j.bbapap.2016.06.014

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 518

  YeoS. C.HoP. C.LinH. S. (2013). Pharmacokinetics of pterostilbene in Sprague-Dawley rats: the impacts of aqueous solubility, fasting, dose escalation, and dosing route on bioavailability.Mol. Nutr. Food Res.571015–1025. 10.1002/mnfr.201200651

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 519

  YoshinoH.KimuraA. (2006). Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study).Amyotroph. Lateral Scler.7241–245. 10.1080/17482960600881870

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 520

  YoshinoJ.BaurJ. A.ImaiS. I. (2018). NAD+ intermediates: the biology and therapeutic potential of NMN and NR.Cell Metab.27513–528. 10.1016/j.cmet.2017.11.002

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 521

  YuY.SyF. C.CallaghanB. C.GoutmanS. A.BattermanS. A.FeldmanE. L. (2014). Environmental risk factors and amyotrophic lateral sclerosis (ALS): a case-control sutdy of ALS in Michingan.PLoS One9:e101186. 10.1371/journal.pone.0101186

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 522

  YunY. C.JeongS. G.KimS. H.ChoG. W. (2019). Reduced sirtuin 1/adenosine monophosphate-activated protein kinase in amyotrophic lateral sclerosis patient-derived mesenchymal stem cells can be restored by resveratrol.J. Tissue Eng. Regen. Med.13110–115. 10.1002/term.2776

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 523

  YusufM.KhanM.RobaianM. A.KhanR. A. (2018). Biomechanistic insights into the roles of oxidative stress in generating complex neurological disorders.Biol. Chem.399305–319. 10.1515/hsz-2017-0250

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 524

  ZewenL.ZhangpinR.JunZ.Chia-ChenC.EswarK.TingyangZ.et al (2018). Role of ROS and nutritional antioxidants in human diseases.Front. Physiol.9:477. 10.3389/fphys.2018.00477

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 525

  ZhangB.WangX. Q.ChenH. Y.LiuB. H. (2014). Involvement of the Nrf2 pathway in the regulation of pterostilbene-induced apoptosis in HeLa cells via ER stress.J. Pharmacol. Sci.126216–229.

  • Pubmed Abstract
  • Google Scholar

• 526

  ZhangH.RyuD.WuY.GarianiK.WangX.LuanP.et al (2016). NAD+ repletion improves mitochondial and stem cell function and enhaces life span in mice.Science3521436–1443. 10.1126/science.aaf2693

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 527

  ZhangL.ZhouG.SongW.TanX.GuoY.ZhouB.et al (2012). Pterostilbene protects vascular endotelial cells against oxidized low-density lipoprotein-induced apoptosis in vitro and in vivo.Apoptosis1725–36. 10.1007/s10495-011-0653-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 528

  ZhangN.SauveA. A. (2018). Regulatory effects of NAD+ metabolic pathways on sirtuin activity.Prog. Mol. Biol. Transl. Sci.15471–104. 10.1016/bs.pmbts.2017.11.012

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 529

  ZhangY.CookA.KimJ.BaranovS. V.JiangJ.SmithK.et al (2013). Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits mt1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis.Neurobiol. Dis.5526–35. 10.1016/j.nbd.2013.03.008

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 530

  ZhongN.XuJ. (2008). Synergistic activation of the human MnSOD promoter by DJ-1 and PGC-1alpha: regulation by SUMOylation and oxidation.Hum. Mol. Genet.173357–3367. 10.1093/hmg/ddn230

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 531

  ZhouY.ZhengJ.LiY.XuD. P.LiS.ChenY. M.et al (2016). Natural polyphenols for prevention and treatment of cancer.Nutrients8:E515. 10.3390/nu8080515

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 532

  ZhuX. H.LuM.LeeB. Y.UgurbilK.ChenW. (2015). In vivo NAD assay reveals the intracelular NAD contents and redox state in healthy human brain and their age dependences.Proc. Natl. Acad. Sci. U.S.A.1122876–2881. 10.1073/pnas.1417921112

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 533

  ZordokyB. N.RobertsonI. M.DyckJ. R. (2015). Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases.Biochim. Biophys. Acta18521155–1177. 10.1016/j.bbadis.2014.10.016

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 534

  ZufiríaM.Gil-BeaF. J.Fernández-TorrónR.PozaJ. J.Muñoz-BlancoJ. L.Rojas-GarcíaR.et al (2016). ALS: a bucket of genes, environment, metabolism and unknow ingredients.Prog. Neurobiol.142104–129. 10.1016/j.pneurobio.2016.05.004

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 535

  ZuoL.ZhouT.PannellB. K.ZieglerA. C.BestT. M. (2015). Biological and physiological role of reactive oxygen species –the good, the bad and the ugly.Acta Physiol.214329–348. 10.1111/apha.12515

  • Pubmed Abstract
  • CrossRef
  • Google Scholar