Natural products targeting cellular processes common in Parkinson's disease and multiple sclerosis

The hallmarks of Parkinson's disease (PD) include the loss of dopaminergic neurons and formation of Lewy bodies, whereas multiple sclerosis (MS) is an autoimmune disorder with damaged myelin sheaths and axonal loss. Despite their distinct etiologies, mounting evidence in recent years suggests that neuroinflammation, oxidative stress, and infiltration of the blood-brain barrier (BBB) all play crucial roles in both diseases. It is also recognized that therapeutic advances against one neurodegenerative disorder are likely useful in targeting the other. As current drugs in clinical settings exhibit low efficacy and toxic side effects with long-term usages, the use of natural products (NPs) as treatment modalities has attracted growing attention. This mini-review summarizes the applications of natural compounds to targeting diverse cellular processes inherent in PD and MS, with the emphasis placed on their neuroprotective and immune-regulating potentials in cellular and animal models. By reviewing the many similarities between PD and MS and NPs according to their functions, it becomes evident that some NPs studied for one disease are likely repurposable for the other. A review from this perspective can provide insights into the search for and utilization of NPs in treating the similar cellular processes common in major neurodegenerative diseases.


Introduction
Parkinson's disease (PD), characterized by striatonigral and dopaminergic degeneration and the Lewy body formation, is a major neurodegenerative disorder affecting mainly elderly people (1), while multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) and the commonest neurological disabling disease inflicting young adults (2).Historically, PD and MS were considered movement disorders, as the former affects the direct and indirect pathways of basal ganglia that are key to the facilitation of movements, while the latter, with damaged myelin sheaths, axonal loss, and sclera formation, impairing the transmission of action potential and hardening multiple muscles (3,4).Some other non-movement symptoms are also shared between these two diseases, which include impaired cognition, atrophy, and depression (5).
Although the etiology/pathophysiology of these two diseases appears to be distinctive, mounting evidence suggests that they are caused by exogenous antigens capable of infiltrating toxins or cytokines across a leaky blood-brain barrier (BBB) (6)(7)(8).Clinically, patients with MS or other immune disorders were found to have a 33% higher risk of developing PD (9).Genetically, 17 loci on chromosomes are shared by PD and MS (10).Neuroinflammation and oxidative stress (OS) cause cell death, contributing to the ultimate etiologies of PD and MS (11,12).As shown in Figure 1, T cells, macrophages, and dendritic cells (DCs), along with pro-inflammatory cytokines such as interleukin 6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α), and reactive oxygen/nitrogen species (ROS/RNS), penetrate the BBB from the peripheral to activate astrocyte and microglial cells.In the presence of cytokines and chemokines, the astrocyte and microglial cells are activated, eliciting a cascade of cellular processes (6,7).For example, in PD brain α-synuclein (α-syn) becomes misfolded to produce highly neurotoxic oligomers and fibrils (13).The oligomers impact on the integrity of cell membrane, resulting in the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) (14).α-Syn aggregates, which are a major component in the Lewy body, also accumulate at activated microglia (15), further wreaking havoc to neurons.In these dying neurons, damaged mitochondria in turn produce additional ROS to aggravate the situation (16).In MS, neuroinflammation and OS gradually destroy oligodendrocytes, eventually leading to a significant loss of myelin sheaths and the underlying axons in areas as diverse as the brainstem, spinal cord, and optical nerves (17).To offset these damages, cellular defense systems are often stimulated.For example, in MS regulatory T (T reg ) and Th2 cells secrete anti-inflammatory cytokines such as IL-10 and transforming growth factor (TGF)-β to suppress neuroinflammation (18,19).In both PD and MS, the Nrf2/Kelchlike ECH-associated protein1 (Keap1) pathway (20) is important for upregulating antioxidative proteins and redox molecules that counteract OS initiated by ROS/RNS.
Because different brain regions are compromised in PD and MS and some cellular processes vary, the clinical modalities are different.Unfortunately, many clinical drugs for PD and MS exhibit limited efficacy and have toxic side effects.One remedy is to resort to the use of natural products (NPs), on the basis that they generally have few side effects.Moreover, many of them are either ingredients in traditional medicines or have been used to treat other neurological disorders, cancers, and diseases related to inflammation (36)(37)(38).
Many reviews have summarized the results of using NPs for treating PD, MS, or other neurodegenerative diseases according to their molecular structures (34,(38)(39)(40)(41)(42)(43)(44).To our knowledge, few categorized based on their functions toward cellular and subcellar processes inherent in both PD and MS.No reviews have linked the use of NPs for PD to those utilizing the same or similar type of NPs as MS modalities.The motivation behind our attempts to review the NP modalities for both PD and MS stems from the abovementioned similarities and the general belief that therapeutic advances against one neurodegenerative disorder is likely to be useful in targeting the other (45,46).Both PD and MS have multifactorial traits in their etiology/pathophysiology and molecular mechanisms.Therefore, we focus on those NPs that possess multiple therapeutic effects.Specifically, we emphasize on NPs that are antioxidative/anti-neuroinflammatory, as these properties can help ameliorate both PD and MS (cf. Figure 1).Owing to the limited scope of a mini-review, both NPs and the many cellular and subcellular events reviewed herein are not exhaustive.Furthermore, we only described results that delineated the specific function(s) of each NP and did not include complex mixture in which the role of each species was not elucidated.

NPs targeting di erent pathways or cellular processes
Below we review some findings about the efficacy of select NPs for the various pathways and processes shown in Table 1 and Figure 2, respectively, with emphases placed on the modalities of NPs in counteracting neuroinflammation and OS.We describe the functions and modes of actions of different NPs in the order of names enclosed in the boxes of Figure 2, beginning with those in the shaded area (common in both PD and MS) and progressing to those related only to PD (shown at the top of the figure) and only to MS (encompassed by the dashed box).

PD and MS
Mainly in PD Mainly in MS

Protection against neuroinflammation
(-)-Epigallocatechin-3-gallate (EGCG), a polyphenol abundant in green tea, can downregulate inducible NO synthase (iNOS) and TNF-α expression, and inhibit neuronal death via direct modulation of microglial activation both in SH-SY5Y and in primary rat mesencephalic cultures employed for studying PD (48).It also diminishes IL-6 and IL-1β in LPS-induced rats (48), and reduce the 6-OHDA-induced expression of TNF-α and IL-1β in SK-N-AS cells (49).EGCG also shows anti-inflammatory function toward MS patients and EAE mice (50, 51).The EGCG treatment reverses clinical severity in EAE by modulating the ratio of M1/M2 macrophages both in vivo and in vitro, with decreased levels of pro-inflammatory cytokines and increased levels of transforming growth factor (TGF)-β (52).Besides, it reduces the levels of phosphorylated NF-κB p65 in M1 macrophages (53).
Curcumin, a polyphenol extract from turmeric, inhibits the secretion of inflammatory cytokines in lipoteichoic acid-induced microglial cells (57) and transforms microglia into the M2phenotype (58,59).Additionally, immunomodulatory properties of curcumin were observed in treating MS and EAE (60,61).Its treatment reduces the clinical severity of EAE by modulating T cell differentiation, with decreased levels of Th1 and Th17-related factors and increased levels of Th2 and T reg responses (18).Besides, FIGURE Summary of NPs studied for di erent cellular processes in PD and MS, with the names of NPs used for the same and di erent processes in PD and MS shown in black and red, respectively.NPs studied thus far only for PD are shown in green, while those only for MS in brown.The shaded area contains processes related to inflammation and OS common in both diseases, whereas the top unshaded area depicts some extensively studied processes inherent in PD and the unshaded area encircled by the dashed box shows myelin protection and regeneration, which are unique of MS.The names of some clinical drugs targeting di erent processes are listed in italic.For PD, levodopa (L-Dopa), monoamine oxidase (MAO) inhibitor (rasagiline and selegiline), catechol-O-methyl transferase (COMT) inhibitor (tolcapone and entacapone) and DA agonists (ropinirole and pramipexole) are employed ( ).In MS, methylprednisolone, glatiramer acetate, interferon-β b, fingolimod, and teriflunomide are used ( ).
it increases the expression of TGF-γ-coding genes in the EAE mice (61).
Other anti-inflammatory phenolic compounds include ellagic acid (EA) and its metabolites such as urolithins A (UA) and B (UB), which decreases the NO level and suppressing expression of cyclooxygenase (COX)-2 and other cytokines in LPS-treated BV2 microglial cells (62).The UA treatment reduces the loss of dopaminergic neurons, ameliorating neuroinflammation in the MPTP mice (63).In addition, EA protects brains of 6-HODA rats (64) and MPTP mice (65) against neuroinflammation.Besides PD, EA has been reported to ameliorate demyelination, reduce MS severity and partially restore tissue levels of TNF-α, IL-6, IL-17A, and IL-10 in EAE rodents (66).
6-Gingerol, a substance in ginger, was found to significantly inhibit 6-OHDA-induced cell apoptosis of PC12 cells through the MAPK pathway (67), and suppresses expressions of TNF-α, IL-6, and iNOS in LPS-induced astrocytes and rats (68).Moreover, in the EAE mouse mode 6-gingerol inhibits the DC activity and Th17 polarization, resulting in induction of tolerogenic DCs (69).Some flavonoids were found to inhibit the NF-κB pathway.Baicalein, an extract from the plant Scutellaria baicalensis, reduces cytokine production in LPS-activated BV2 cells and inhibits the expression of COX-2 and NF-κB/p65 (70).It mitigates the NLRP3/caspase-1/GSDMD pathway in both MPTP (71) and rotenone (72) mouse models.For MS, baicalein alleviates disease severity by reducing Th1 and Th17 cell migration and impairing microglia activation (73), and improves cuprizone-induced EAE mice by inhibiting the ionized calcium binding adapter molecule 1 (Iba1)-positive microglia (74).Furthermore, it decreases levels of CXCR6 + CD4 + , CD8 + , and Th17 cells in EAE mice (75).Another study showed that it inhibits the M1 macrophage but promotes the M2 macrophage by modulating the STAT1 level (76).Hesperidin, abundant in the citrus fruits, shows efficacy in decreasing many cytokines depicted in Figure 2 in the MPTP mice (77).It also increases the production of IL-10 and TGF-β to confer protection to MS mice (78).Kurarinone, an NP from only in Sophora flavescens, is reported to attenuate the MPTP-mediated neuroinflammation (79).In addition, it inhibits clinical progression of EAE by decreasing levels of several pro-inflammatory cytokines and preventing Th1 and Th17 cell differentiation and proliferation (80).
Other NPs possessing anti-neuroinflammatory properties have only been studied for either PD or MS.Chlorogenic acid, a major component in coffee, inhibits the NF-κB pathway and suppresses IL-1β, IL-6, and TNF-α release in LPS-induced microglia (92).Its supplementation mitigates motor dysfunction in MPTP mice and increases IL-10 (93).Quercetin, present in flowers, leaves, and fruits of many plants, has been shown to suppress inflammatory cytokine levels in LPS-induced primary microglia, zebrafish, and mice, as well as rotenone-induced mice (94).Garcinol, a tri-isoprenylated benzophenone isolated from Garcinia sp., is capable of reducing inflammatory markers in the SNpc of MPTP mice (95).Ginkgolide K (96-98) and oleanolic acid (OA) (99) have the same functions in EAE mice by modulating T cell and macrophages/microglia differentiation.

Protection against OS
EGCG can react with ROS and activate the Nrf2 signaling pathway (48).It inhibits MPP + -induced OS in PC12 cells via the SIRT1 pathway, and increases glutathione level and mitigates the OS-induced cell death in L-Dopa-treated PC12 cells (48).Moreover, it reduces the NO level and lipid peroxidation in rotenone-induced PD rats (100) and prevents paraquat-induced OS in Drosophila (101).In the EAE model, EGCG reduces the ROS level and modulates macrophage subtypes (52).It also directly suppresses M1 macrophage differentiation with lower level of iNOS in vitro (52).
Resveratrol was demonstrated to activate the Nrf2 pathway in the brain of rotenone-induced rats (102), and attenuate OS via the Nrf2/Keap1 pathway in a microglia cell line (103).Curcumin was found to enhance Nrf2 expression and stability, thereby resisting OS and reducing apoptosis in H 2 O 2 -treated RAW264.7 cells (104).Additionally, it reduces ROS in paraquat-induced SH-SY5Y cells to enhance cell survival (105).EA can inhibit Keap1 to accumulate Nrf2 in the nucleus, which alleviates the impact of ROS on neuronal cells.EA can prevent DA neuron degeneration from OS in MPTP mice (65), reduce ROS level, and reverse the superoxide dismutase and catalase activities in the cuprizone-induced demyelination model ( 106).
Other compounds also exhibited antioxidant activities.Baicalein (107), hesperidin (108), quercetin (109), caffeine (110), piperine (85), Ginkgolide K (97), and naringin ( 111) can all activate the Nrf2 pathway, modulate macrophage differentiation, or reduce OS both in cells and in animals.Crocin reduces OS and attenuates damage to dopaminergic neurons in MPTP mice (112).In addition, it inhibits the level of lipid peroxide and increases the total antioxidant capacity in MS patients (91).OA alleviates detrimental effects in EAE mice by reducing lipid peroxidation and superoxide anion accumulation (99).Our group demonstrated that ginnalin A, a polyphenol from the red maple, is a ROS scavenger and can activate Nrf2-regulated antioxidant defense system in SH-SY5Y cells (113).

Natural products targeting processes inherent in PD and in MS
NPs have also been used as potential therapeutics targeting processes specific to PD or MS, as depicted by the areas at the top of Figure 2 and encompassed by the dashed box, respectively.We briefly review these aspects as follows.
NPs have been identified to inhibit the formation of αsyn oligomers and fibrils, disaggregate aggregates into non-toxic Frontiers in Neurology frontiersin.orgforms, or disrupt their interaction with lipid membranes.EGCG was demonstrated to inhibit fibrillation and disaggregate fibrils, thus enhancing cell survival (48).Curcumin can prevent α-syn aggregation in LPS-induced PD model (117).Baicalein was shown to inhibit fibrillation of the wild-type α-syn and disaggregate fibrils, as one of us found with his co-workers (118).It can also disrupt fibrils of an α-syn mutant (119).Crocin can inhibit αsyn aggregation and disassemble mature fibrils (120).We found that ginnalin A is effective in disrupting the oligomerization and fibrillation of both α-syn and amyloid-β peptides (121), in line with the finding that an NP effective in inhibiting the aggregation of one amyloid species is often capable of acting the same way on another.Alkaloids such as synephrine and trigonelline can also inhibit seed-induced α-syn aggregation, increasing cell viability of SH-SY5Y (122).Squalamine (123) and trodusquemine (124) were reported to inhibit lipid-and fibrilinduced α-syn aggregation and alleviate α-syn toxicity to cells.They also showed promising treatment results in animal model studies (124,125).Many NPs can modulate autophagy to counteract protein misfolding/aggregation and to attenuate cell death and PD symptoms.Curcumin can enhance autophagy and rescue chloroquine-treated SH-SY5Y cells (105).A chronic caffeine treatment was demonstrated to selectively reverse α-syninduced autophagy defects in PD mouse striata (126).Ursolic acid, a triterpenoid compound in fruit peels, also promotes autophagic clearance and ameliorates symptoms in rotenoneinduced mice (127).Glycyrrhizic acid was reported to alleviate 6-HODA and corticosterone-induced neurotoxicity in SH-SY5Y cells by modulating autophagy (128).Trehalose (129), a disaccharide in some fungi, and maysin (130), the most abundant C-glycosilflavone in corn silk, counteract α-syn toxicity via autophagy induction.

Preservation and regeneration of myelin
EA promotes oligodendrocyte maturation, decreases oligodendrocyte apoptosis, and decreases demyelination and axonal loss in EAE (66).Additionally, EA, UA, and UB increase the expression of sphingolipids in human oligodendroglioma cells, rendering neuroprotective effects (131).Piperine facilitates myelin repair, suppresses astrocyte activation, and increases the expression of neurotrophins, i.e., brain-derived neurotrophic factor (BDNF) and myelin basic protein (MBP), to attenuate clinical features of the lysolecithin-induced demyelinated model (132).Crocin increases the level of MBP, preserving myelination and axonal density in EAE (90).Ginkgolide K maintains the integrity of myelin and promotes regeneration in EAE via the Nrf2 pathway (97).
Ursolic acid, similar to EA, decreases CNS demyelination, preserves axonal integrity, increases the level of ciliary neurotrophic factor (CNTF), and promotes myelin regeneration in a PPARγ-dependent manner (133).Moreover, it enhances myelin repair in EAE mice by promoting the expression of OPC marker transcription factors (134), and alleviates the symptom of cuprizone-induced EAE mice by modulating the IGF-1 expression (135).

Protection of BBB
The MS pathogenesis is concomitant with BBB dysfunction, leading to permeation of inflammatory factors across BBB into brain.Resveratrol was found to protect the BBB integrity in EAE mice by suppressing the level of tight junction proteins and inhibiting the expression of adhesion factors ICAM-1 and VCAM-1 (136).Dietary naringenin preserves the BBB integrity in EAE by inhibiting the level of tight junction-associated factors including ZO-1 and occluding (137).Ginsenoside-Rg3-enriched Korean red ginseng extract (Rg3-KRGE) also preserves the BBB integrity, increases the levels of zonula occludens-1, claudin-3, claudin-5, platelet endothelial cell adhesion molecule-1, and fibronectin, and inhibits the level of MMP-9 in EAE by modulating the NADPH oxidase pathway (138).Matrine upregulates the expression of occludin, claudin 5, and tight junction proteins, and attenuates EAE severity (139).These functions are analogous to those of some drugs used currently in clinical settings, which are denoted in italics in the box at the bottom right of Figure 2.

Conclusions
The diverse functions of the select NPs organized in Figure 2 and reviewed herein bode well with many beliefs in the field while revealing some interesting trends.First, PD and MS share many characteristics, especially in terms of neuroinflammation and OS.It is therefore not surprising that NPs capable of ameliorating PD symptoms have similar effects on MS.In this regard, to select NPs targeting a cellular/subcelluar process of one disease, one can draw on the knowledge of NPs that had been investigated for the same process of the other.A large stockpile of NPs has been examined thus far for only PD or only MS.At least some of them can be repurposed reciprocally or even for other neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis.Second, among the countless NPs, special attention should be given to those that have displayed efficacy in modulating/intervening multiple cellular processes and signaling pathways, owing to the complexity of both PD and MS.Third, from Figure 2 it is apparent that even an NP possessing different functions is incapable of counteracting all the detrimental effects inherent in the many factors or processes.Thus, the combined use of multiple NPs might be needed for regulating the different pathways.Fourth, NPs have shown great promise in addressing the pathological processes for which no clinical drugs are available.Even for processes that have been dealt with by clinical drugs, NPs offer as alternatives to afford equally effective treatments without severe side effects.Finally, an increasingly accepted notion in the PD field is that inflammation is significantly manifested.In particular, increased levels of pro-inflammatory cytokines, activation of the immune cells, and their infiltration through a more permeable BBB are hallmarks being recognized.As these processes have long been studied in the MS field, many NPs and their known functions are likely translatable to PD research and modalities.As the research continues to progress from cellular and rodent models to primates and patients, it is foreseeable that the vast pool of NPs should afford at least a few highly effective therapeutics with low or little toxicity.

FIGURE
FIGURESchematic illustration of PD and MS pathogeneses triggered by neuroinflammation and OS, with an emphasis placed on their commonalities.The red and green arrows represent the neuronal lesions and repairs, respectively.The upper half of the scheme (above the dashed blue line) is related to PD and the lower half is specific to MS.

TABLE Cell
signaling pathways involved in PD and/or MS.