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) (6–8). 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/Kelch-like ECH-associated protein1 (Keap1) pathway (20) is important for upregulating antioxidative proteins and redox molecules that counteract OS initiated by ROS/RNS.

Thus far, experiments on humans and other primates are limited for both diseases. For PD, disease models are created in animals such as rodents, zebrafish, Caenorhabditis (C.) elegans, and Drosophila (21). Commonly used neurotoxins are 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), paraquat, and rotenone (21). Genetic manipulation of PD-related genes, such as α-syn (SNCA) and protein deglycase (DJ-1), are used in transgenic models (21, 22). PD models induced by inflammatory species such as lipopolysaccharide (LPS) are also employed (23). For MS, the mouse model is used, and the predominant one is the experimental autoimmune encephalomyelitis (EAE), along with cuprizone- and lysolecithin-induced demyelination models (24).

Several cell signaling pathways are related to PD, MS, or both, as listed in Table 1. Nuclear factor-κB (NF-κB) (25), mitogen-activated protein kinase (MAPK) (26), and Janus kinase/signal transducers and activators of transcription (JAK/STAT) (27) all contribute to neuroinflammation. Neuroinflammation is capable of inducing the cell apoptosis and/or pyroptosis pathways such as the nod-like receptor pyrin domain-containing protein 3 (NLRP3)/caspase-1/gasdermin D (GSDMD) (28) and the silent mating type information regulation 2 homolog (SIRT1) (29) pathways in PD and the peroxisome proliferator-activated receptor γ (PPARγ) (30) pathway in MS, which inhibits the NF-κB pathway and stimulates Nrf2 expression to counteract OS. Similarly, the NADPH oxidase pathway also causes OS via the production of ROS (31). We should note that these signaling pathways are not independent but interconnected. For instance, NF-κB pathway displays dual effects on OS (32) and Nrf2 can inhibit NF-κB activation (33). Mitochondrial dysfunction is closely linked to PD and other neurodegenerative diseases. Consequently, the peroxisome regulated-activated receptor gamma coactivator-1 alpha (PCG-1α)-NRF-mitochondrial transcription factor A (TFAM) or PCG-1α-NRF-TFAM pathway is generally impacted, leading to impaired oxidative metabolism and mitochondrial biogenesis (34, 35).

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 (36–38).

Many reviews have summarized the results of using NPs for treating PD, MS, or other neurodegenerative diseases according to their molecular structures (34, 38–44). 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.

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).

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.

XX, CH, and PW collected materials. FZ formulated the review structure. The first draft of the manuscript was written by XX, CH, and PW. A revision was finalized by FZ and PW. All authors read and approved the final manuscript.