Parkinson’s disease is the most common neurodegenerative movement disorder characterized by progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) along with widespread intracellular aggregates of the protein α-synuclein (Thome et al., 2016; Pinto et al., 2018). Twenty genetic variants have been identified by human genetic studies, which are linked to PD pathogenesis (Pan et al., 2017). Currently monogenetic PD accounts for 3–5% of total cases of PD (Ben-David and Tu, 2015). PARK genes are most commonly linked to pathogenesis of PD and the inheritance patterns may be autosomal dominant such as in case of PARK 1, 3, 5, and 8 or autosomal recessive as in case of PARK 2, 6, and 7 (Hamza et al., 2010). The basic features of PD include tremors at rest, rigidity, bradykinesia, gait, and balance dysfunction (Patel et al., 2014). It has been observed that PD is found in all ethnic groups but geographical differences exist is prevalence of disease. Approximately 1–2% of the population suffers from PD over the age of 65 years and this figure increases to 3–5% in people of 85 years and older (De Lau and Breteler, 2006; Alves et al., 2008). The incidence rate of PD is 8–18 per 100,000 person-years. The rate of incidence is lower in Asian countries than in western countries (Tan, 2013; Lee and Gilbert, 2016). It is also documented that prevalence of PD will be almost double by 2030 and the burden of disease will also shift from developed western countries to developing eastern nations (Dorsey et al., 2007).

Although no successful therapies are currently available that can modify the disease. However, dopaminergic medications are the mainstay of treatment for symptomatic relief of motor symptoms (AlDakheel et al., 2014; Rizek et al., 2016). The available medications that are currently in practice for management of PD include levodopa, dopamine agonists (ropinirole, bromocriptine, cabergoline), MAOIs (selegiline), amantadine, anticholinergics (trihexyphenidyl), carbidopa, and entacapone (Nakaoka et al., 2014; Pagano et al., 2015). Levodopa is the most efficacious to control motor symptoms of the disease and is drug of choice to initiate first in course of treatment (Connolly and Lang, 2014). Other medications indicated for control of non-motor symptoms are clozapine and quetiapine for psychotic symptoms, SSRIs, TCAs, and SNRIs for depression, rivastigmine for dementia, BZs and non-BZ hypnotics for insomnia, and fiber-rich diet for constipation (Todorova et al., 2014). There are certain limitations to the use of anti-Parkinson’s medications especially to efficacious classes of drugs. Dopaminergic medications including levodopa are most commonly associated with psychosis, motor complications, and impulsive compulsive disorder (Rascol et al., 2003; Weiss and Marsh, 2012). Most of the patients with PD develop motor complications and dyskinesia within 5–10 years of levodopa treatment (Bãjenaru et al., 2016).

Polyphenols are most abundant antioxidant phytochemicals present in human diet. They are secondary metabolites present in foods and beverages of plant origin including fruits, vegetables, cereals, herbs, spices, legumes, nuts, olives, chocolate, tea, coffee, and red wine (Fantini et al., 2015). Polyphenols possess antimicrobial, anti-inflammatory, antiviral, anticancer, and immunomodulatory activities (Marzocchella et al., 2011; Benvenuto et al., 2013). Polyphenols could be divided in different classes depending on chemical skeleton of compound including phenolic acids, flavonoids, stilbenes, and lignans (Li et al., 2014; Kim et al., 2016). Polyphenols are capable of crossing blood–brain barrier and control neuronal disease pathogenesis at molecular and symptomatic level (Bhullar and Rupasinghe, 2013). The neuroprotective effects of polyphenols/natural compounds have been documented in various neurological disorders (Ayaz et al., 2015, 2017a,b; Ahmad et al., 2016; Patel et al., 2017; Rauf et al., 2017a,b; Farooq et al., 2018; Khan et al., 2018) including cerebral ischemia, brain edema, PD, amyotrophic lateral sclerosis, brain tumors, and cognitive impairments (Jagla and Pechanova, 2015). Their neuroprotective activities are attributed to their antioxidant potential, anti-inflammatory actions, and alteration of signaling pathways (Basli et al., 2012; Moosavi et al., 2016). While managing neurodegenerative, novel therapeutic strategies support the application on antioxidant polyphenols as monotherapy or antioxidant cocktail formulation (Vecchia et al., 2015).

Silymarin is the polyphenolic flavonoid extracted from dried fruit of Silybum marianum and is most commonly used for hepatoprotective activities since ancient times (Wang et al., 2015; AbouZid et al., 2016). Among phytochemicals it is one of the most widely used flavonoid because of its extensive therapeutic properties (Mady et al., 2016). Silymarin has been indicated in pathological conditions of various origins such as prostate, lungs, CNS, pancreas, and skin. It is considered safe at therapeutic doses but improper administration of dosages may lead to cause adverse drug reactions (ADRs) where gastrointestinal effects are more common among them (Karimi et al., 2011). Neuroprotective effects of silymarin have been studied in various models of neurological disorders such as Alzheimer’s disease, PD, and cerebral ischemia. Reducing oxidative stress, inflammatory cytokines, altering cellular apoptosis machinery, and estrogen receptor machinery are mechanisms that are responsible for neuroprotection by silymarin (Borah et al., 2013). Additionally because of poor aqueous solubility the bioavailability of silymarin is low and only 23–47% of silymarin reaches systemic circulation after oral administration (Yang et al., 2013). The aim of the present study is to provide comprehensive review of the recent literature exploring the effects of silymarin administration on progression of PD. Our primary focus is on the chemical basis of pharmacology of silymarin and its anti-Parkinson’s mechanisms.

Silymarin is a mixture containing isomer flavonolignans (silybin, isosilybin, and silychristin), small number of flavonoids (taxifolin), fatty acids, and other polyphenolic compounds. It is a lipophilic agent extracted from seeds of S. marianum. Silybin comprises 50–70% of silymarin having greatest degree of biological activity (Ghosh et al., 2010; El-Elimat et al., 2014). Seeds of S. marianum also contain other flavonolignans including isosilybin, dehydrosilybin, desoxysilychristin, desoxysilydianin, silandrin, silybinome, silyhermin, and neosilyhermin (Karkanis et al., 2011). Flavonolignans present in the mixture of silymarin contain flavonoid moiety links to a molecule of lignin moiety (coniferyl alcohol) (Crocenzi and Roma, 2006). The molecular formula of flavonolignan skeleton is C₂₅H₂₂O₁₀ and molecular weight is 482. Pelter and Hansel were first who established the structure of silybin in 1975 (Lee and Liu, 2003). It has been documented that silybin is a mixture of diastereoisomers namely silybin A and silybin B. Silybin also known as silibinin contains 1,4-dioxane ring in addition to flavonoid moiety and is a most active anti-hepatotoxic agent. It has been reported that the presence of 2,3-double bond in the C-ring of flavonoid structure results in increasing antioxidant activity of silybin (Ahmed et al., 2003; Ramasamy and Agarwal, 2008; Khan et al., 2011).

Silymarin (Figure 1) is a pharmacologically active phytochemical extracted from seeds and fruits of S. marianum, commonly known as milk thistle (Wagoner et al., 2010; Wang et al., 2015). S. marianum is an annual or a biennial plant and is a member of plant family Asteraceae (Table 1). The genus Silybum contains two species that are S. marianum and Silybum eburneum. Geographically this plant distributes around the globe. It is cultivated in Mediterranean region, Sinai, Afghanistan, and has been neutralized in other parts of the world (Karkanis et al., 2011; AbouZid et al., 2016). It has been used from ancient times where Theophrastus (4th century B.C.) was probably first to describe it under the name Pternix. The initial use of S. marianum was reported by Dioscorides for treatment of serpent bites. In 1898, the use of herb to relieve obstructions of the liver was documented by British herbalist Culpepper (Post-White et al., 2007; Karkanis et al., 2011). Today, it is one of the most commonly used botanical supplement in the world. As reported in 2012, it ranked sixth in total US botanical supplement sales (Kawaguchi-Suzuki et al., 2014).

The neuropathological mechanisms (Figure 2) responsible for pathogenesis of PD include protein misfolding, disrupted protein handling, mitochondrial dysfunction, oxidative stress, impaired calcium handling, and neuroinflammation (Brundin and Melki, 2017). The substantia nigra (SN) and ventral tegmental area (VTA) are major dopaminergic nuclei located in mid-brain playing most important functions of brain. The progressive loss of dopaminergic neurons in SN pars compacta and dopaminergic denervation in forebrain areas is the main characteristic of motor symptoms of PD (Politis, 2014; Jovanovic et al., 2018). There is also non-dopaminergic neuronal loss contributing to non-motor symptoms of PD. These neurons include monoaminergic cells in the locus coeruleus and raphe nuclei, cholinergic cells in the nucleus basalis of Meynert, pedunculopontine tegmental nucleus, and hypocretin cells in the hypothalamus. Loss of cholinergic cells, pedunculopontine tegmental nucleus, and hypocretin cells are associated with cognitive dysfunction, gait problems, and sleep disorders, respectively, as seen in PD. It has been reported that the presence of 140 amino acid containing proteinaceous α-synuclein-rich inclusions called as Lewy bodies exclusively in neurons is closely related with neuronal loss in PD (Leverenz et al., 2009; Jowaed et al., 2010; Obeso et al., 2010; Surmeier et al., 2017).

Several factors either from genetic background or environmental factors play a crucial role in cellular α-synuclein misfolding. Mitochondrial dysfunction, oxidative stress, failure of liposomal autophagy, ubiquitin proteasome system, and neuroinflammation are factors responsible for α-synuclein misfolding and cell-to-cell transfer of pathogenic α-synuclein assemblies (Brundin and Melki, 2017). α-Synuclein pathology is a neurotoxic process in which the formation of oligomers occurs from soluble α-synuclein monomers, which then combines to form large insoluble α-synuclein fibrils (Kim and Lee, 2008; Melki, 2015). Liposomal autophagy and ubiquitin proteasome are both responsible for α-synuclein degradation and thus impairment of these degradation systems can contribute to α-synuclein accumulation (Xilouri et al., 2013; Kaushik and Cuervo, 2015). Like other neurodegenerative disorders, formation of reactive oxygen species (ROS) is a key mechanism in pathogenesis of PD causing degeneration of dopaminergic neurons. Metabolism of dopamine, mitochondrial dysfunction neuroinflammation, high level of iron and calcium in SN pars compacta, and aging all are contributing factors in the generation of ROS. At mitochondrial level, the electron transport chain is the major contributor in causing oxidative stress. Other sources of ROS formation are monoamine oxidase (MAO), NADPH oxidase, and other flavo-enzymes along with nitric oxide (NO). Lipid peroxidation also occurs under oxidative stress as brain contains high concentration of polyunsaturated fatty acids. Mutations in α-synuclein, parkin, PINK1, DJ-1, and LRRK2 are related to mitochondria and thus studies linked these mutations with oxidative stress (Dias et al., 2013; Yan et al., 2013).

Neuroinflammation may not be an initial trigger, but it is one of the most essential factor in pathogenesis of PD. As documented, catecholaminergic and dopaminergic neurons express MHC-I proteins which can expose them to cytotoxic T-cell-mediated death in the presence of antigens. Activation of complement system on Lewy bodies pre-exposes neurons to inflammatory processes (Loeffler et al., 2006; Poewe et al., 2017). Glial cells activation in SN pars compacta has been reported concurrently with an increased expression of pro-inflammatory mediators. CCAAT/enhancer binding protein ß (C/EBPß) is a transcription factor whose role in pathogenesis of PD has been reported. It regulates the expression of genes involved in inflammatory processes and brain injury (Morales-Garcia et al., 2017). Studies suggest important role of cyclooxygenase-2 (COX-2) enzyme in secondary activation of microglia, in the progression of the inflammatory response, and in the progressive loss of dopaminergic neurons (Vijitruth et al., 2006).

Silymarin is a polyphenolic flavonoid with strong antioxidant activities and is in clinical practice for management of hepatic disorders. Free radicals scavenging, elevating cellular glutathione level, and improving activity of superoxide dismutase are key mechanisms attributed to antioxidant activities of silymarin. Through inhibition of oxidative stress, silymarin possesses neuroprotective effects and it can be used in the management of neurodegenerative disorders including Alzheimer’s disease, PD stroke, and traumatic brain injury (Kittur et al., 2002; Chtourou et al., 2010; Muley et al., 2012; Pandima Devi et al., 2017). It has been reported that silymarin inhibits the activation of microglia as well as production of inflammatory mediators such as tumor necroses factor-alpha (TNF-α) and NO, as a result reducing damage to dopaminergic neurons (Křen and Walterova, 2005; Kaur et al., 2011). As reported, silymarin maintained striatal dopamine levels by diminishing apoptosis in the SN and preserving dopaminergic neurons. Studies linked these effects with antioxidant and anti-inflammatory potential of silymarin (Abushouk et al., 2017). It has been also documented from some studies that silymarin reduces level of α-synuclein protein and increasing dopamine level (Srivastava et al., 2017).

Different researchers have extensively investigated the molecular mechanisms of silymarin in various experimental models of neurological and PD (Figure 3).

Silymarin is a polyphenolic phytochemical with promising therapeutic potential. It is extracted from dried fruit of S. marianum and has been used as a hepatoprotective agent since long time. Later-on, the beneficial role of silymarin in the treatment of pathological conditions of various origins including cancer has been studied and documented. It is a mixture of flavonolignans with strong antioxidant and anti-inflammatory activities. It also has binding affinity with estrogen receptor β in CNS regions which attenuates neurotoxicity and prevents lipid peroxidation. These effects make silymarin a valuable choice in therapeutics of neurodegenerative disorders such as PD. Additionally, it has shown significant neuroprotective effects in various in vitro and in vivo models. However, because of low aqueous solubility the bioavailability of silymarin is quite low i.e., 23–47%. Several techniques are available to improve the bioavailability of silymarin such as SMEDDS, solid dispersions, PSNs, and liposomes. Moreover, the bioavailability issue can be resolved via chemical derivatization. Thus, further research is required on these grounds in order to get molecule of clinical utility for the treatment of PD.

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.