Antioxidative Role Of Traditional Chinese Medicine in Parkinson’s Disease

Fahim Muhammad a,1 , Yan Liu b,1 , Yongtao Zhou c,d , Hui Yang e , Hongyu Li a,b,*

a College of Life Sciences, Lanzhou University, Lanzhou, China

b School of Pharmacy, Lanzhou University, Donggang West Road No. 199, Lanzhou, 730020, China

c Department of Neurology, Xuanwu Hospital of Capital Medical University, Beijing, China

d Clinical Center for Parkinson's Disease, Capital Medical University, Beijing, China

e Institute of Biology Gansu Academy of Sciences, China

Contact: joanna.jia@wecistanche.com / WhatsApp: 008618081934791

Ethnopharmacological relevance: Neuroprotective Traditional Chinese Medicine (TCM) has been practiced in alternative medicine from early days. TCM-derived neuroprotective compounds, such as Chrysin, Cannabidiol, Toonasinoids, and β-Aaron, exert significant effectiveness's towards Parkinson's disease (PD). Further, these neuroprotective TCM (Traditional Chinese Medicine) showed antioxidative, anti-inflammatory, anti-tumor, anti-septic, analgesic properties. Recent research showed that the reduction in the reactive oxygen species (ROS) decreased the α-synuclein (α-syn) toxicity and enhanced the dopaminergic neuron regenerations, the main hallmarks of PD (Parkinson's disease). Therefore, the neuroprotective effects of novel TCM (Traditional Chinese Medicine) due to its antiradical activities needed deep investigations.

Aims of the study: This review aims to enlighten the neuroprotective TCM (Traditional Chinese Medicine) and its components with their anti-oxidative properties to the scientific community for future research.

Method: The relevant information on the neuroprotective TCM (Traditional Chinese Medicine) was gathered from scientific databases (PubMed, Web of Science, Google Scholar, ScienceDirect, SciFinder, Wiley Online Library, ACS Publications, and CNKI). Information was also gained from MS and Ph.D. thesis, books, and online databases. The literature cited in this review dates from 2001 to June 2, 0201.

Results: Novel therapies for PD (Parkinson's disease) are accessible, mostly rely on Rivastigmine and Donepezil, offers to slow down the progression of disease at an early stage but embraces lots of disadvantages. Researchers are trying to find a potential drug against PD, which is proficient at preventing or curing the disease progress, but still needed to be further identified. Oxidative insult and mitochondrial dysfunction are thought to be the main culprit of neuro- degenerations. Reactive oxygen species (ROS) are the only causative agent in all interactions, leading to PD (Parkinson's disease), from mitochondrial dysfunctions, α-syn aggregative toxicity, and DA neurons degeneration. It is evident from the redox balance, which seems an imperative therapeutic approach against PD and was necessary for the significant neuronal activities.

Conclusion: Our study is explaining the newly discovered TCM (Traditional Chinese Medicine) and their neuroprotective and antioxidative properties. But also bring up the possible treatment approaches against PD (Parkinson's disease) for future researchers.

Keywords: Parkinson's disease, Reactive oxygen species, Traditional Chinese Medicine, Alpha-synuclein, Dopaminergic neuron

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1. Introduction

Parkinson's disease (PD) is the world’s second progressive neuro-degenerative and a common, chronic disorder after Alzheimer's disease (AD). PD (Parkinson's disease) is an age-related neurodegenerative disorder with approximately 1% prevalence in people over age 60 and 4% of the population above age 85 (Wright Willis et al., 2010). The main factors involved in initiating PD (Parkinson's disease) are dopaminergic (DA) neurons degenerations and α-synuclein (α-syn) accumulations in the substantia nigra par compact (SNPs) of the brain. PD (Parkinson's disease) causes tremors, stiffness, and slowing of movements (Hirsch et al., 2016; Kalinderi et al., 2016; Van Den Eeden et al., 2003). According to statistics, PD affects 0.3% of the entire population in industrial countries, while the pervasiveness shows an increment of ~1% of the population over age 60 (Zou et al., 2014). At the same time, the reported PD incidence rates are 8–18 per 100K individuals every year. For the past 60 years, PD onset showed a severe increment in prevalence rates (Fig. 1). Through worldwide meta-analysis data, the PD incidence rate is about 40 times more dominant in individuals aged ≥80 than in those aged 40–49 (de Lau and Breteler, 2006). Usually, PD is exceptional in individuals <40 years old (Chong et al., 2015). But patients are apt to live with the disease for many years due to its slow and progressive nature (Trinh and Farrer, 2013). Therefore, the vast spreading rate of PD tends to be high in the elderly (i.e., 80 years of age).

Furthermore, research showed that PD (Parkinson's disease) is higher in male populations than in females (Lin and Farrer, 2014). The difference was calculated statistically between two age groups (49–59) (Blandini, 2013). But the difference between genders was comparatively more minor between the ages of 49–59 and much more significant in people around age 80 (Li et al., 2011). One of the main leading causes of PD (Parkinson's disease) is reactive oxygen species (ROS), which actively degenerate DA neurons and enhance the α-syn protein misfolding as toxic intracellular entities (Wang et al., 2015; Yan et al., 2013). Considering PD’s societal demands and economic burden on affected families encourages the neurobiologist to urgently identify and develop neuroprotective therapeutic drugs with anti-oxidative properties.

Fig. 1. Describing a summary about the prevalence of PD (Parkinson's disease) in the Chinese population in comparison with Europe and also showing a meta-analysis of worldwide PD prevalence, including cost per PD patient.

1.1. Variations in PD signs and symptoms

The supreme distinctive motor functions include bradykinesia, rigidity, rest tremor, and postural uncertainty. The non-motor features consisted of psychiatric symptoms, cognitive impairment, olfactory dysfunction, and autonomic dysfunction (Li et al., 2011). Therefore, many PD (Parkinson's disease) sub-categories, including postural instability and tremors linked with cognitive failures, difficulty in predictions, and higher dis- ease advancements (Su et al., 2021). Additional subtypes suggest diverse pathogenic mechanisms and development for several PD (Parkinson's disease) traits (Surmeier et al., 2017). Neuropathologically, PD is categorized by neuronal loss, associated with α-syn accumulation as Lewy bodies (LB) and cytoplasmic inclusions, particularly in the brainstem and cortical regions of the brain (Poewe et al., 2017). Current studies showed that oxidative stress, protein mishandling, and mitochondrial dysfunction play a vital role in the pathogenesis of sporadic PD. These methods are persuaded by non-genetic factors, possibly in interactions with susceptible genetic factors (Lu et al., 2017). Hence, awareness is needed regarding non-genetic factors to comprehend the disease pathogenesis and improve therapeutic strategies effectively (Lu et al., 2013). A vast, well-planned, and future populace-based group study is suited to examine the effectiveness of several potential risk factors and their associations (Wang et al., 2011). Oxidative stress (OS) has a crucial role in neurological disorders; lately, special attention has been paid to OS in several brain diseases, including PD. In reality, excessive production of ROS at mitochondrial electron transport chain (ETC) sites is considered the emerging cause of neuronal death (Bohnen and Albin, 2011). Till now, there is not any permanent cure for PD, and treatment is generally symptomatic. Recently available treatment approaches for neurodegenerative diseases target only a small portion of the population, merely reducing the disorders’ symptoms and failing to prevent disease progressions (Selikhova et al., 2009). Therefore, scientist moved their interest towards neuroprotective TCM ( Traditional Chinese Medicine) with anti-oxidative properties to prevent and cure the PD progression via targeting free radical species production in mitochondrial ETC to reduce the OS.

1.2. Mitochondrial dysregulation and PD (Parkinson's disease)

Mitochondria illustrate vital roles in an organism’s cell’s lives and death. Mitochondria performed varieties of main regulatory developments in organisms cells: ROS generations (Han et al., 2020), apoptotic cells death (Tamtaji et al., 2020), calcium homeostasis (Elyasi et al., 2020), amino acid and nitrogen metabolism, ATP productions, heme, and iron-sulfur biosynthesis and detoxification (De Virgilio et al., 2016; Kulisevsky et al., 2013). Mitochondria supplies a vast amount of cellular energies in ATP form by oxidative phosphorylation cycle; due to this cycle, electrons are transferred from cofactors by complexes I–IV, situated in the inner mitochondrial membrane (Yang et al., 2020). At various sites of mitochondrial ETC, ROS can be generated, particularly on complex I to III, where electrons hardly leak to oxygen and make a superoxide anion (O2.-) to produce ROS in mitochondria (Yamaguchi et al., 2020). Mitochondria are the primary site of ROS productions at the cellular level, with about 1–4% of mitochondrial O2 intake transformed to ROS (Ahmed et al., 2021). Besides, in the ETC, enzymatic reactions occur containing enzymes α-ketoglutarate dehydrogenase that produces superoxide. Maximum cellular superoxide converted to H2O2, either by redox reaction or spontaneous dismutase (Akanji et al., 2021). H2O2 is a stable and membrane-permeable, reactive free radical, relatively has a long shelf life, and allows diffusions within cells. As a redox-active species, H2O2 can injure some enzymes by oxidizing their thiol groups. H2O2 can be perished by mitochondrial antioxidant and cytosolic systems. It can generate the reactive hydroxyl (OH) radicals in the existence of Fe+2 cations by the Fenton reactions (Bento-Pereira and Dinkova-Kostova, 2021). Because of strong OH oxidizing potential can harm the macromolecule (DNA and protein) at the sites of origin. Later, OH groups become a tremendously hazardous element for the organism via mitochondrial dysregulation, a significant cause of PD (Parkinson's disease).

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1.3. ROS and PD

The ROS generation by NO synthase is associated with a range of harmful behaviors. Mitochondria are also a source of ROS, which appears to contribute to aging and neurodegenerative diseases. Other instances to generate ROS are metal complexes, cytochrome P450, and monoamine oxidase (Yan et al., 2013). Oxidative DNA damaging due to ROS is one of the apparent entities in PD (Parkinson's disease) (Chen et al., 2020). The leading cause of neuronal cell death is mitochondrial dysfunction and OS. Subsequently, therapeutic approaches that improve ROS and upgrade mitochondrial functions in preventing PD (Parkinson's disease) are thoroughly explained in the current scenario. ROS, such as hydroxyl radicals, hydrogen peroxide, and superoxide, are continuously produced in aerobic organisms. In normal physiological conditions, the ROS production level is in equilibrium with the capacity of antioxidants. OS is a major threat for the central nervous system (CNS), particularly owing to the high consumption of oxygen and also its enrichment in polyunsaturated fatty acids, making it susceptible to lipid peroxidation. These are the few factors that cause the enhancement of ROS production in PD (Fu et al., 2020). Injuries from OS have been associated with the pathogenesis of neurodegenerative diseases, including PD (Parkinson's disease) and various other related disorders (Fig. 2). PD (Parkinson's disease) shares various pathological features, comprising abnormal protein depositions (α-Syn) linked with microglial activations and alterations in tissues’ redox balance to induce ROS (Angelova, 2021). That’s the reason how PD (Parkinson's disease) contributes to enhancing ROS pro- ductions. These methods are persuaded by non-genetic factors, possibly in interactions with susceptible genetic factors (Ghosh et al., 2020). Hence, awareness is needed regarding non-genetic factors to comprehend the disease pathogenesis and improve therapeutic strategies effectively. While Complex I deficiencies in the mitochondrial respiratory chain, dysregulation of neural apoptosis generations, DA neurons degenerations, and genetic mutations of LRRK2, SNCA, PINK1, all are possible causes of ROS formation in PD (Dorszewska et al., 2021). As a fact, excessive ROS production participation causes oxidative stress. Oxidative stress has been associated with PD pathogenesis (A et al., 2020). Large volumes of anti-oxidants are needed to attain defensive effects in the CNS of PD patients. Besides, anti-oxidant administration is inadequate to eliminate ROS toxicity at high doses, resulting in a small therapeutic window open in the neurological disorder. This highlighted the need for alternative approaches to counteract therapeutically and neutralize ROS’s detrimental effects. Then to restore the cellular redox balance via antioxidative properties from herbal medicine (Zeng, 2017).

Fig. 2. Possible mechanisms of action of mitochondrial dysfunction via ROS leading to PD (Parkinson's disease).

1.4. Oxidative stress (OS) and PD (Parkinson's disease)

OS is a key mechanism of neurological disorders that can directly harm to CNS. OS is the cascade reaction characterized by significant augmentations of oxidized compounds. These enhanced compound oxidations disturbed the oxygen demands and decreased the antioxidants. Therefore, unstable, and cytotoxic molecules called free radicals (ROS) are produced. The small amount of ROS does not cause damage and coordinates with the body’s anti-oxidant system to maintain normal homeostasis. The anti-oxidants are represented by anti-oxidant enzymes as ROS protection factors, e.g. catalase (CAT), superoxide dismutase (SOD), and glutathione-S-transferase (GST); while the non-enzymatic anti-oxidant factors comprise carotenoid, melatonin, and microelements (Blesa et al., 2015). These factors unite with each other to protect from ROS injuries. Enzymes like SOD usually function in association with non-enzymatic anti-oxidant factors, which are called co-factors, and established anti-oxidation shelters to neutralize free radicals, and thus restore normal inner homeostasis. However, once ROS overwhelms the cellular anti-oxidant activity, OS occurs, leading to the accumulation of cytotoxic compounds that result in enzyme failure, proteins (α-Syn) disordering, and lipids oxidations (Sarrafchi et al., 2016). Further, OS leads to the destruction of the DA neuronal tissues in SNPc, which is significant in PD (Parkinson's disease) pathogenesis. There is no doubt, in CNS, OS makes a significant contribution as oxidative damage to lipids, proteins, and DNA. But polyunsaturated fatty acids are the most prone to lipid per- oxidation, and OS severely impacts the function of lipids to maintain the membrane fluidity and permeability. Similarly, the DNA damage by OS alters its coding properties at transcriptions or interferes with normal metabolic functions and this damage occurs mostly at post-translational modifications (Narne et al., 2017). As a result, a few PD-causing genes like PINK1, DJ-1, PARKIN, LRRK2, and SNCA generated and influence the mitochondrial functioning to cause ROS generation vulnerable to OS. Therefore, cellular homeostatic methods like mitophagy and ubiquitin-proteasomes are also under the influence of OS (Desai et al., 2018). The interaction between various genetic and sporadic mechanisms contributes to neurodegeneration due to oxidative reactions leading to OS, damaging vital cellular pathogenic proteins (α-syn), and causing DA neurons degeneration (Fig. 3). Therefore, various monogenic forms of PD (Parkinson's disease) have been discovered with mutations in leucine-rich repeat kinase-2 (LRRK2). LRRK2 is the most common cause of sporadic and genetic PD. LRRK2 is a complex protein with catalytic domain mutations implicated in the pathogenesis of PD (Parkinson's disease) (Shah et al., 2018). The common G2019S mutation is associated with increased kinase activity and causes defects in autophagy, cytoskeletal structure, and synaptic vesicle transport. Recently, it is observed that LRRK2-G2019S induces OS and injuries via mitochondrial anti-oxidants inactivation which are capable of regulating LRRK2 actions at the mitochondrial level. Hence anti-oxidants are required to maintain the oxidative environment and minimize the ROS injuries at the mitochondrial level (Ramos-Gonzalez et al., 2021). Herbal drugs are the major source of anti-oxidants, including various other compounds which participated in reducing ROS production on treatment, for example, plant-based flavonoids (Table 1).

Fig. 3. Depicting the possible mechanism of oxidative stress via ROS leading to PD (Parkinson's disease). ROS generated at mitochondrial ETC via a redox reaction. Due to the lack of anti-oxidants, excessive ROS generated and disturbed the SNCA, PINK-1, DJ-1, and LRRK-2 to form α-Syn protein. This genetic mutation impaired the protein degradation pathways via the inactivation of lysosomal machinery, and as result, α-Syn accumulations cause Lewy body dementia, an initial form of oxidative stress. Furthermore, excessive production of ROS also imbalanced the anti-oxidative defense system in the cells and led the iron accumulations. This accumulation of iron causes damage to dopamine metabolism. In short, the figure explains ROS’s initial role via various pathways to generate oxidative stress, which is a leading cause of PD (Parkinson's disease) in neuronal cells.

1.5. α-Syn and PD (Parkinson's disease)

Mitochondrial-associated protein α-syn participated in mitochondrial energy productions and biogenesis generally linked to PD (Parkinson's disease) pathogenesis (Ryan et al., 2015). The fibrillar, oligomeric, and insoluble α-Syn are neurotoxic proteins affected by several factors. Lewy body formulae and Lewy neurites in the neurons of PD (Parkinson's disease) patients are aggregated inclusions of α-syn (Lashuel et al., 2013). These α-syn accumulations play a major role in PD progressions and enhance the threat of Lewy body dementia (Mittal et al., 2017). In PD patient brain tissues study, α-syn protofibrils and oligomers are highly upregulated (Duffy et al., 2018). α-syn can bind and localize with mitochondrial membrane and interrupt the functions. Several factors acting on α-syn structure comprise post-translational modifications and genetic mutations (Ono et al., 2011). Besides, α-syn lessening complex I and III activities in mice mitochondrial inner membrane suggest a close affiliation between mitochondria and α-syn functions via lipid metabolism regulations (Ferrer et al., 2011). α-syn mutations (A30P and A53T) in the mitochondrial inner membrane are responsible for the phospholipids’ amphiphilic ability, leading to mitochondrial dysfunction by stopping the complex I activity (Guardia-Laguarta et al., 2014). In vivo, α-syn A30P mutation might contribute to oxidative damage in mitochondria and triggers mitochondrial apoptosis (Kleiner et al., 2021). These oxidative and nitrative effects on α-syn residues promoted the abnormal α-syn aggregations. While, mutations of LRRK2, DJ-1, Parkin, and PINK1 recognized in the PD genetics stimulated the accumulations of α-syn, triggering oxidative stress and disturbing the neuron’s internal homeostasis environment (Shah et al., 2020). While α-Syn toxicity mechanisms on mitochondria membrane stay subtle, a provocating indication is that mitochondrial dysfunction might be the first factor involved in neurotoxic aggregations of α-Syn in the DA neuron of SNPc. Recently, research conducted in Mito-Park mice confirmed that mitochondrial DNA damage is involved in the formations α-syn aggregations next to Lewy body formations. Inclusively, there is likely a mutual relationship between α-syn aggregated pathology and mitochondrial dysfunctions while DJ-1 LRRK2, PINK1and PARKIN mutations are involved in the α-syn pathological advancements (Ryan et al., 2015). Besides, previous research described the beneficial effects of α-syn at the cellular level rather than its detrimental effects mentioned above. It showed that in particular conditions, α-syn acts as a helpful protein for cells’ lives. This happens when endogenous α-syn is counteracted with intoxication methamphetamine. While, the dysregulation of the cysteine-string- alpha chaperone protein leads to cells pathology, which is countered by α-syn over-expression. In series with this, α-syn upregulation expressions protected the cells from oxidative dopamine damage. Furthermore, α-syn shortening, together with β- and γ-synuclein depletions, modified the structure and function of the brain (Oueslati et al., 2015; Ryskalin et al., 2018).

1.6. Dopaminergic (DA) neurons and PD (Parkinson's disease)

DA is a neurotransmitter under physiological conditions and shows an integral role in locomotory movement, learning, and memory (Mishra et al., 2018). DA is also one of the most widely deliberated neurotransmitters in the brain due to its contribution to neurological and numerous mental disorders. In the CNS of mammals, midbrain dopaminergic neurons are the primary source of producing DA. DA group cells function for the brain’s identification and localization via histo fluorescence (Beaulieu and Gainetdinov, 2011). DA is anatomically and functionally situated in the mesencephalon and diencephalon of the brain region (Carmichael et al., 2021). This brain region consisted of nearly 90% of the DA brain cells. Most likely, the very popular is the nigrostriatal system, which originates in SNPc. The SNPc pathway plays an essential function in controlling voluntary motor movements (Speranza et al., 2021). DA neurons are related to >1% of the total number of brain neurons and play a significant part in regulating various features of a simple brain. Likely, they are involved in motor behaviors, motivations, and working memory (Walton et al., 2020). In DA neurons toxicity, oxidative stress plays a dominant role via mitochondrial dysregulation, the leading cause of PD (Parkinson's disease) (Ferrazzoli et al., 2020). TCM (Traditional Chinese Medicine) played a vital role in recovering degenerative DA neurons via anti-oxidative properties as a part of traditional prescription in medical history (Chen et al., 2007). Earlier research confirmed that TCM with anti-oxidative properties endorses improved 6-OHDA exposed DA neurons in various PD models and impaired memory functions (Zhang et al., 2015; Zou et al., 2014). The previously used neuroprotective TCM with multiple properties mentions below.

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2. Previous therapeutic targets of neuroprotective TCM with anti-oxidative properties against PD (Parkinson's disease)

Ginkgo biloba [G. biloba] is a very popular TCM (Traditional Chinese Medicine), and its extracts widely used to treat memory impairment disorders for a long time (Li et al., 2020). Pre-treatment of G. Biloba extract diminished DA neurons degeneration in experimental rats intoxicated with a neurotoxin 6-hydroxydopamine (6-OHDA), dose-dependently (Guo et al., 2015; Ren and Zuo, 2012). Further extract of G. Biloba improved the motor deficits, enhanced muscular coordination, neutralized the lipid peroxidation by-products, and restored the glutathione (GSH) in the SNPc. While G. Biloba extract pre-treatment recovered catalases and superoxide dismutases (SOD). EGb761 is a component from G. Biloba and significantly improved dysfunctions in mice intoxicated by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Besides, EGb761 markedly reduced MPTP-induced loss of dopamine levels in the brain (B ajenaru et al., 2021). The neuroprotective effect of EGb761 against MPTP-treatment was associated with the reduction of ROS generations and inhibitions of lipid peroxidation (Yin et al., 2021). Similarly, pre-treatment of With ania somnifera [W. Somnifera] extract showed anti-oxidative properties in 6-OHDA-treated PD (rat’s) models (Rajput et al., 2017; Sengupta et al., 2016). In another study, co-administration of Centella Asiatica extract in MPTP treated rats significantly recovered the MPTP induced toxicity in oxidative biomarkers and enhanced the numbers of anti-oxidants enzyme in the striatum and hippocampus (Haleagrahara and Ponnusamy, 2010). Furthermore, Rhizoma Curcuma longa in Chinese Jiang Huang on treatment significantly inhibited the MPTP-generated GSH reduction and lipid peroxidation and improved the SOD expressions and SNPc (Jurenka, 2009). Similarly, Quercus dentata (Q. dentata) in Chinese [Hu shu] is a famous TCM and significantly attenuated the degenerations via 6-OHDA-exposure in PD (Parkinson's disease) rat’s models (Taib et al., 2020). In addition, Q. dentate on treatment reduced the mitochondrial ROS generations, improved the SOD, and glutathione peroxidase (GPx) expression compared with control groups (Lee et al., 2020). Further Pre-treatment of quercetin improved the motor balance and the signal coordination in the experimental mice treated with MPTP and significantly reduced the level of 4-hydroxy-2-nominal (4-HNE) in the SNPC of the brain compared with control groups. Besides, quercetin extract possessed anti-oxidative properties, significantly reduced ROS productions, and enhanced SOD expressions in the brain (Benameur et al., 2021; Gomes et al., 2014). Radix Scutellaria (R. Scutellaria) in Chinese [Huang qin] is one of the effective TCM (Traditional Chinese Medicine) drugs widely used to treat dementia in the elderly. For instance, R. Scutellaria protected dopamine neurons against toxin and improved motor function in MPTP-treated laboratory mice dose-dependently. While, R. Scutellaria restored the expressions of the anti-oxidant biomarker in the striatum of the brain (Gaire et al., 2014; Zhao et al., 2020). In PD (Parkinson's disease), apoptosis has been considered as the main mechanism of DA neurons death. Several initiators and executioner’s caspases intervene in apoptosis. Initiator caspase-9 activation mediated the intrinsic pathway famously called the mitochondrial-mediated pathway. Similarly, caspase-8 activation mediated the extrinsic apoptotic pathway known as the cell death receptors mediated pathway. Both initiator caspases unite into a single pathway of executioner caspases and comprise caspase-3 and caspase-6. Therefore, executioner caspases activation leads to the apoptosis morphological features, such as DNA subsequent fragmentations. Accumulated studies showed the anti-apoptotic property of few Chinese herbal extracts. These anti-apoptotic properties of TCM (Traditional Chinese Medicine) play a very important role in eradicating PD and its progressions. For example, Pre-treatment of Ginsenoside (Rg1) a component-based drug from Radix ginseng in Chinese called [Ren shen] enhanced the anti-apoptotic Bcl-2 protein and Bcl-2 mRNA, and reduced the pro-apoptotic Bax, Bax mRNA expressions in MPTP-treated mice (Lee et al., 2012; Zhou et al., 2014). In another study, Herba Cistanche (H. Cistanche) in Chinese [Rou Cong Rong] stopped the dopamine reduction and improved motor function on treatment in the MPTP-exposed mice. Moreover, H. Cistanches decreases the MPTP-induced activation of pro-apoptotic caspase-3 and caspase-8 signaling pathways (Li et al., 2016). While Fructus Mori (F. Mori) in Chinese called [Sang Shen] extract study in MPTP-intoxicated mice showed that it significantly improved the motor deficit and reduced the mitochondrial ROS generations compared with a control group (Deng et al., 2014; Kim and Oh, 2013). In vitro study, Mulberry fruit extract on treatment protected the SHSY5Y cell lines via inhibiting the apoptotic signaling pathway (Liu et al., 2020; Tam et al., 2021). Similarly, extract of Radix Notoginseng (R. Notoginseng) in Chinese [San Qi] on treatment diminished α-Syn expression and controlled the pro-caspase-3, pro-caspase-9 caspase-12, and pro-apoptotic signaling expressions compared with the control group. Furthermore, R. notoginseng promoted the molecules with anti-oxidative stress properties and inhibited pro-inflammatory enzymes expression in rats of PD models (Lan et al., 2012). Radix chuanxiong (R. chuanxiong) in Chinese [Chuan xiong], is a very popular TCM and has been extensively used to cure kidneys, heart, and brain diseases for hundreds of years (Chen et al., 2019; Zeng, 2017). Administration of tetramethylpyrazine bis-nitrone (TN-2), a derivative from R. chuanxiong, to MPTP-exposed rats for 14-days prevented the dopamine reduction compared with a control group (Zeng et al., 2018). Further, TN-2 on treatment controlled the dysfunctions of Bcl-2 and Bax expressions and activated the caspase proteins (Jin et al., 2014).

Similarly, Radix Salviae Miltiorrhizae (R. S. Miltiorrhizae), in Chinese [Danshen], is a well-known traditional herb used extensively to treat neurodegenerative diseases for thousands of years. Tanshinone I is one of the major bioactive flavonoids of R. S. Miltiorrhizae. Modulation of microglial over-reaction may signify a novel therapeutic target to lessen the advancement of neurological disorders. Tanshinone I has been evaluated to reduce the neuro-inflammation on treatment via inhibiting the mRNA expression of TNF-α, IL-1β, iNOS, and release of TNF-α and nitric oxide (NO) in lipopolysaccharide (LPS)-activated microglial pathway (Phung et al., 2020).

While microglial activation can provide neuroprotection through inhibition of neuro-inflammations. This cellular neuroinflammation has been associated as one of the causative factors for various neurodegenerative diseases like PD (Parkinson's disease). Sphingolipid metabolic pathway (SMP) plays a significant role in cell proliferation, survival, chemotaxis, and neuroinflammation in peripheral macrophages. Sphingosine kinase1 (SphK1), a vital enzyme of the SMP, and its receptors are expressed in microglial cells of mice, where SphK1 changes the expressions of nitric oxide pro-inflammatory cytokines in microglia exposed with LPS. LPS treatment improved the SphK1 mRNA and protein expressions in microglia. Suppression of SphK1 by its inhibitors diminished mRNA expression of iNOS, TNF-α, IL-1β, and release of TNF-α and nitric oxide (NO) in LPS-activated microglia (Jiang et al., 2020).

Moreover, the addition of sphingosine 1 phosphate (S1P), a breakdown product of sphingolipid metabolism, increased the expression levels of TNF-α, IL-1β, and iNOS and production of TNF-α and NO in activated microglia. Therefore, to summarize, suppression of SphK1 in activated microglia inhibits the production of pro-inflammatory cytokines and NO, and the addition of exogenous S1P to activated microglia enhances their inflammatory responses. Besides, the chronic pro-inflammatory cytokine production by microglia has also been involved in SphK1 modulation, S1P, and neuro-inflammation (Yuan et al., 2020). Therefore, sphingolipid metabolism under the TCM (Traditional Chinese Medicine) treatment could look upon as a future potential therapeutic approach in the control of neuroinflammation to cure neurodegenerative disorders (Rahman et al., 2021).

As mentioned above, all of the TCM (Traditional Chinese Medicine) and their neuroprotective roles via following the various mechanisms against PD (Parkinson's disease) played a significant role in the neurological sciences. But the study on them is not enough to fulfill the actual requirement of PD to prevent or completely eradicate. Therefore, brain researchers worldwide are working on neuroprotective substances and extracts from herbal drugs to discover the effective treatment against PD. Consequently, it is an urgent and challenging task in basic sciences and clinical medicine to develop a new synthetic or locate a natural drug for treating neurodegenerative disorders. Dopamine-based replacement therapies consist of dopamine precursors; however, unfortunate effects may appear in the future for long-term use (Wu et al., 2021). Novel pharmacotherapy and cell replacement therapies routinely used before on human models need extensive evaluations (Zhu et al., 2021).

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3. Recently discovered neuroprotective TCM with anti-oxidative properties against PD (Parkinson's disease)

The current accessible treatment approaches for neurological disorders target only a small portion of the individuals, hardly improve disease symptoms and fail to stop advancement. US Food and Drug Administration (FDA)-approved drugs against PD (Parkinson's disease), such as Rivastigmine and Donepezil, decrease the PD (Parkinson's disease) symptoms and slow down the advancement, but unsafe for long-term use. Treatment of L-DOPA improved the motor symptoms of PD (Parkinson's disease) in most patients but often caused motor complications, recognized as L-DOPA-induced dyskinesia due to its long-term use. The currently available FDA-approved drugs to treat PD (Parkinson's disease) are resistant to antimalarial and antibiotics, other than the cardiovascular and endocrine systems. All such problems with the current treatments ultimately lead to permanent disability or death of patients. Several pharmacological methodologies are being examined, involving a natural extract from TCM (Traditional Chinese Medicine) to convey an advantageous effect against PD (Guo et al., 2007). Anti-parkinsonism conventional drugs effectively upgrade PD symptoms during the several initial years of onset in patients as mentioned above (Prasad and Hung, 2021). PD patients occasionally suffer less from non-motor symptoms (depression, anxiety, and irritability). While, in other ways, highly suffer from motor fluctuations like sensory, neuropsychiatric, gastrointestinal, and autonomic signs, including fatigue, pain, and sleep disturbances. These motor and no motor symptoms are possibly the results of treatment with dopaminergic mediators (Rota et al., 2020). Various studies have recognized that the PD motor symptoms are conjoint in all stages with the fundamental division of quality of life (Meloni et al., 2020). TCM (Traditional Chinese Medicine) has a long history of applications worldwide and is gradually considered an alternative medicine to eliminate disorders via various approaches (Matos et al., 2021; Ren and Zuo, 2012). Long history, extensive use, old tradition, and a maximum number of medical records with no side effects highlight the overall worth of TCM (Traditional Chinese Medicine). For a couple of years, research on the relationship between active components (prescriptions) of TCM and neurodegenerative diseases has been published in many SCI journals. This news encourages scientists to understand the mechanisms of TCM with a new perspective of research, conferring a novel theoretical basis for clinical applications. The exact molecular mechanism of action of TCM with anti-oxidative properties against neurological diseases is still under investigation and needs to be researched at full scale. However, optimization of ROS production via the Nrf2 anti-oxidative pathway, which participates in the output of PD via DLB (Lewy Bodies dementia), is well-thought-out to be the primary goal of these TCM products (Ji, (2021); Ji et al., 2021a,b). A promising candidate from the neuroprotective TCM with anti-oxidative properties required neutralizing ROS-mediated damaging via stimulating endogenous antioxidant enzymes localized in the CNS. These enzymes comprised peroxiredoxins, catalases, and superoxide dismutases (Schreibelt et al., 2007; van Muiswinkel et al., 2005). Cytoprotective proteins transcription is controlled by the Nrf2 nuclear transcription factor, which plays a key part in cellular redox reactions regulations (Nguyen et al., 2004). However, on ROS exposure, Nrf2 detaches from cytoplasmic Keap1. Then it translocates into the nucleus’s nucleoli, attaching it to the anti-oxidant response elements of the gene’s promoter regions and encoding the antioxidant enzymes (Nguyen et al., 2003). Similarly, numerous xenobiotics comprising 1, 2-dithiole-3-thione, tertbutyl hydroquinone, sulforaphane, and dimethyl fumarate imitate transient oxidative signals endorsing the Nrf2-driven anti-oxidant enzymes transcription (Itoh et al., 2003). In this paper, we review the involvement of neuroprotective TCM with anti-oxidative properties to diminish ROS-induced injury in PD pathology by following the putative protective Nrf2-induced anti-oxidant generated pathway (Clements et al., 2006) Table 1. Besides, previously neuroprotective TCM exhibited anti-apoptotic activities via enhancing the Bcl-2 and reducing the Bax expressions at mRNA level on treatment (Li et al., 2014; Xue et al., 2014). In addition, these neuroprotective TCM activated the autophagy pathways and eliminated the abnormal protein toxicity at the cellular level in SNPc (Ting et al., 2018). OS describes destructive procedures resulting from an imbalance between ROS formation and limited anti-oxidant defenses. Due to enhanced ROS production and/or impaired antioxidant defense, disturbance in the cellular redox balance eventually leads to oxidative alterations of biological macromolecules, such as proteins, lipids, and nucleic acids (Ganie et al., 2016).

The investigation has recognized numerous plants that show medicinal properties against neurodegenerative diseases like PD (Parkinson's disease) during the last couple of decades. Names of the recently discovered neuroprotective TCM components have listed in Table 1, with anti-oxidative properties. Therefore, the aim of writing this review article is to discuss some of the significant TCM (Baishao, Shichangpu, Danggui, Shanzhuyu, Heshouwu, Dangshen, Huanglian, Tianma, Zhigancao, Heshouwu, Dangshen, Huanglian, Tianma, Zhigancao, HuangQin) in milieu to their neuroprotective potential with anti-oxidative properties as additional characteristics against DLB and PD (Table: 1) (Ren and Zuo, 2012).

4. Current problems to overcome in PD therapy

Some studies mentioned that TCM (Traditional Chinese Medicine) treatment is involved in post-transcriptional modification at the mRNA level (Lyu et al., 2019). These changes could be beneficial or lead to a dangerous role in PD (Parkinson's disease), needed further investigations on a large scale. For example, G. Biloba leaves extracts are used to treat chronic neurological disorders. Therefore, a high-density microarrays oligonucleotide was applied to describe the transcriptional effects in the cortical and the hippocampus of rat SNPc. Gene expression analysis of mRNAs showed a change more than 3-fold in their expression. In the cortex, mRNAs for microtubule associations and threonine phosphatase were significantly enhanced. The study shows that rat foods supplemented with G. Biloba extract distinguished neuromodulators’ effects in vivo and demonstrated genomic expression changes (Singh et al., 2019). Therefore, further investigation is needed to monitor the biological actions of treated extracts at the post-transcriptional level. While, in another study, splicing of precursor mRNA is an essential step in the post-transcriptional modification of genes expressions, providing significant expansions of the functional proteomes of eukaryotic organisms with limited gene numbers on neuroprotective TCM (Traditional Chinese Medicine) treatment. The average human gene comprises seven introns and eight exons, producing three or more alternative splicing mRNA’s isoforms. Biochemical studies permitted the structural, functional, and compositional analysis of splicing complex at numerous phases within the spliceosomes cycles. Alternative splicing mechanisms include mRNA-protein connections of splicing factors with monitoring sites termed enhancers or silencers. Therefore, mutations that lead to diseases are often found in splice sites near axonic or intron borders or can even happen near RNA regulatory enhancers or silencers elements. Together, these studies provide systematic perceptions of how the spliceosome assemblies, their dynamics, and catalysis occur and how alternative splicing machinery is controlled and progresses by TCM (Fu et al., 2013; Han et al., 2017). Such discoveries make the spliceosome machinery a new and attractive target for TCM (Traditional Chinese Medicine) and its components as therapeutic interventions against PD. Besides, it can be a threat in the form of TCM and its neuroprotective component’s behavioral effects on altering the splicing machinery actions. In the CNS, alternative splicing is an effective mechanism that regulates the functions of the genes (Su et al., 2018), but further study needs to be done on a wide scale under the influence of neuroprotective TCM with anti-oxidative properties in the future.

5. Future therapeutic targets of PD (Parkinson's disease)

5.1. Tyrosine phospho-transferase (Fyn)

Fyn is an Src family non-receptor kinase and is highly associated with brain development, immune system regulations, and cell proliferation. Collectively, pre-clinical studies showed the Fyn progressive role in aspects of PD pathogenesis. It may control phosphorylation of α-syn, DA neurons death induced by OS or improved glutamate and neuroinflammatory excitotoxicity in mediating the signaling pathway. These discoveries suggested that therapeutic targeting of Fyn or its related pathways may characterize a novel methodology against PD (Parkinson's disease) treatment in the future (Angelopoulou et al., 2021).

5.2. Saracatinib

Saracatinib is a non-selective inhibitor of Fyn and has already been verified in clinical trials for Alzheimer’s disease. Therefore, targeting a novel selective role of Fyn inhibitors in PD (Parkinson's disease) could help develop future Fyn-targeted therapeutic strategies under neuroprotective TCM (Traditional Chinese Medicine) (McFarthing et al., 2020).

5.3. Degenerated axon

Degenerated axon is a critical step in the pathogenesis of neurological diseases (Lingor et al., 2012). Cumulative evidence suggested that axonal degenerations occur early in the PD (Parkinson's disease) pathways and represent a promising target for future therapeutic strategies (Cheng et al., 2010).

5.4. Adult hippocampal

Neurogenesis is considered a significant brain part for the progress and treatment of depression and anxiety. Human post-mortem and genetic animal models of PD (Parkinson's disease) studies observed the disruptions of severely hippocampal neurogenesis (Lim et al., 2018). These are all non-motor kinds of related symptoms already seen in PD (Parkinson's disease). Adult hippocampal neurogenesis could lead to a novel therapeutic target against PD for future scientists and provide a promising cure for PD (Agrawal and Schaffer, 2005).

5.5. Heat shock proteins (HSPs)

HSPs recognized as molecular chaperones to support protein folding have lately become a new research target in PD (Parkinson's disease). In PD, the disease pathogenesis is highlighted by misfolded proteins and intracellular inclusion bodies formations (Ebrahimi-Fakhari et al., 2014). Furthermore, HSPs may have anti-apoptotic effects and keep the DA neuron's homeostasis regular against stresses. Therefore, some recent discoveries of novel HSPs inducers suggested that HSPs could be a potential therapeutic target for PD and other neurodegenerative disorders in the future (Erekat et al., 2014).

5.6. CB2 cannabinoid receptor (CB2r)

CB2r is a novel approach for preventing and treating CNS diseases. These receptors were discovered in CNS and the peripheral tissues. Recent studies claim that CB2r could be the PD therapeutic target under the neuroprotective TCM treatment in future studies (Teodoro et al., 2021).

5.7. Peroxisome Proliferator-Activated Receptors (PPARs)

Peroxisome Proliferator-Activated Receptors (PPARs) belong to the nuclear receptor super families’. Previously, in various metabolic procedures, PPARγ is a primary target for insulin sensitizers, comprising glucose homeostasis. While recent studies confirmed the PPARγ activation characteristics in neurogenesis. Therefore in future neurological studies, PPARγ can serve as a potential therapeutic target against PD (Avarachan et al., 2021; Lim et al., 2021).

5.8. Hypoxia

Hypoxia is a condition of low oxygen supply to the brain. Various series of studies pointed out the crucial role of hypoxia in PD (Parkinson's disease) pathogenesis. However, severe hypoxia is harmful to the brain. Herein we are presenting hypoxia, a novel therapeutic target to treat PD (Parkinson's disease) under the neuroprotective influence of TCM (Traditional Chinese Medicine) with anti-oxidative properties (Burtscher et al., 2021).

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6. The possible neuroprotective TCM mechanisms

We are introducing the effects of TCM (Traditional Chinese Medicine) herbs on neural regenerations and their impact on various major ailments of the neurodegenerations, including depressions, cerebral ischemia AD, and PD, which possibly provided the reference for clinical treatments (Bandiwadekar et al., 2021). As a result, a growing number of patients with PD (Parkinson's disease) use complementary and alternative medicine (CAM). The epidemiological data estimated that the frequency of CAM uses for PD is between 25.7 and 76% by seven separate countries (Farr et al., 2020; Redd et al., 2021). Furthermore, TCM (Traditional Chinese Medicine) is one of the primary modules of CAM, playing a vital role in medical care for thousands of years in China against patients with memory impairments and dementia. Chinese herbal medicines mostly belong to pharmacological therapies. Herbal extracts can prevent neuronal loss, and their bioactive compounds comprise anti-inflammatory, anti-apoptotic, and antioxidant effects (Meng et al., 2020; Mohd Sairazi and Sirajudeen, 2020). TCM-based treatments of PD have established various positive outcomes, such as DAT inhibition activities, anti-oxidative stress activities, anti-apoptotic and neuroinflammation inhibitions, augmentation of neurogenesis, elevation in the secretion of neurotrophic factor (NTF), removal of abnormal protein toxicity, and reductions of internal cells ROS generations via its anti-oxidative characteristics in neuronal cells. From the earlier research, some data have been experimented with to evaluate the potential therapeutic advantages of TCM against PD (Parkinson's disease). But their assumptions are unpredictable because of the quality of primary research and less data, so further research needed to be done (Chang et al., 2021).

6.1. DAT inhibition activity

Future Indication has presented that numerous environmental toxins participate in PD (Parkinson's disease) pathogenesis. The neurotoxin-treated PD (Parkinson's disease) models study has identified that the DA transporter (DAT) activity plays an essential role in DA neuron death caused by oxidative stress via the neurotoxins uptake (Chen et al., 2007). Therefore, neurotoxin exposed models are used in neuroprotective studies against PD (Chia et al., 2020). Inhibitory effects of polyphenols from tea on DAT activity were found on the DA neurons in the SNPc of exposed mice models (Prediger et al., 2011). Green tea, a well-known TCM, stops the uptake of 1-methyl-4- phenylpyridinium (MPP+) and 3H-dopamine, protecting DA neurons from vulnerability by inhibiting the DAT activity. Further proof suggested that EGCG can decrease the free radical injuries and oxidative stress by DAT inhibitions in SNPc (Limanaqi et al., 2019).

6.2. Anti-oxidative stress activity

TCM (Traditional Chinese Medicine) and their extracts generally act as anti-OS effects of anti-oxidants. TCM (Traditional Chinese Medicine) anti-oxidant activities were found in Passionflower, Toona Sinensis, Cannabis sativa, Huang qin, Baicalein, Green tea, Ginsenoside, and Curcumin extracts confirmed by in vitro and in vivo research (Ding et al., 2018). For instance, flavonoids reacted as anti-oxidants by scavenging transition metal ions, nitrogen species, and ROS. The extract containing polyphenols from TCM seemed to be non-toxic to the DA neurons of SNPc and protected the DA neurons from oxidative injuries (Javed et al., 2018). The antioxidant moods of flavonoids and polyphenols might be due to the inhibition of nuclear and activator protein-1 and redox-sensitive transcription factors. Glycosides herbal extracts showed anti-oxidant activities, which reduced lipid peroxidations in the rat brain (Lv et al., 2007). It found that by controlling oxidative stress, TCM reduces DA-induced apoptosis in PC12 cells. At the same time, all other neuroprotective TCM with anti-oxidative properties neutralized the ROS generations in various animal PD (Parkinson's disease) models on treatment. For instance, pre-treatment with Chrysin neutralized the DA-induced ROS generations and released the mitochondrial cytochrome-C into the cytosol of the cells (Liu et al., 2015).

6.3. Anti-apoptosis and anti-inflammatory activities

Anti-apoptosis and anti-inflammatory activities are often observed in Ginsenosides, Passionflower, Toona Sinensis, Huangqin, Baicalein, Green tea, and Curcumin extracts. Treatment of these TCM (Traditional Chinese Medicine) extracts on cell lines intoxicated by 6- OHDA reduced NF-kappa B, a prime factor in inflammatory neuronal cell death (Zhang et al., 2017). Baicalein prevented the NF-kappa B and decreased the nitric oxide synthase (iNOS) expression via inhibiting of iNOS promoter for transcription (Qi et al., 2013). Activated microglia are also associated with enhancing the iNOS expression and contribute to the neuroinflammation in DA neurons. Previously discovered TCM (Traditional Chinese Medicine) has verified their effects on activated microglia to decrease the mRNA expression of IL-1β, iNOS, and TNF-α in LPS to stop neuro-inflammation mentioned earlier. This microglial activation pathway could be the therapeutic target to verify the novel drugs against neurological disorders. Moreover, green tea clinical trials showed that NF-kappa B stopped the T-lymphocytes and showed neuroprotection in autoimmune diseases. The neuroprotective role of flavonoids from Chrysin and baicalein from TCM was found by their neuro-inflammatory inhibiting reactions and microglial activation (Song et al., 2020). Later these polyphenol and flavonoids reduced neuro-inflammation-mediated DA neurons degeneration (Li et al., 2005). In Ginsenoside (Rb1, Rb2), the anti-inflammatory effects were detected. This Ginsenoside activated the NF-kappa B and suppressed cyclooxygenase-2 (COX-2) expressions in the mice. Furthermore, the anti-apoptosis and anti-inflammation effects of TCM enhanced the circulations of brain blood in pathological conditions (Xu et al., 2018).

6.4. Neurotrophin-like effects on neurite growths

PC-12 cell lines are the important medium for scrutinizing the PD (Parkinson's disease) disease at the initial stage in the research laboratories. Neuroprotective effects were found in TCM (Traditional Chinese Medicine) extracts like Ginsenoside, passionflower, curcumin, cannabis Sativa, etc. (Xu et al., 2021). Under the presence of nerve growth factors, PC-12 cells grew and were considered control, while the neurotrophic role of different concentrations of Ginsenoside was assessed by analyzing neurite outgrowth. It was observed that this Ginsenoside promoted the neurite outgrowth in the presence of a suboptimal dose of (3–4 ng/ml) NGF for 8d culture. After 18d culture, the Ginsenoside augmented neurites outgrowth in the absence of NGF (Sng et al., 2021).

6.5. NMDA receptors inhibitory activity

The TCM (Traditional Chinese Medicine) herbal extract showed inhibitory effects on receptors NMDA that intercedes neuronal signals or glutamate excitotoxicity. The Rb1 and Rg3 extracted from TCM (Traditional Chinese Medicine) ginseng in the research laboratory significantly prolonged neuronal survival and reduced glutamate-induced neurotoxicity in the mice’s cerebral cortical neurons (Huang et al., 2019). In the hippocampal cells culture, the Rg3 ginseng can hinder the activations of NMDA neurons receptors, signifying that inhibitory effects of NMDA receptors might be one of the novel mechanisms of actions of neuroprotection for various TCM (Ip et al., 2016). An extract of TCM called SY-21 was also observed to exhibit neuroprotection by inhibiting NMDA receptors activities (Dajas et al., 2005). Tyrosine phosphorylation’s, a subunit NR2A of NMDA receptors associated with the activations of NMDA receptors. Administrations of SY-21 inhibited ischemia, leading to elevation of the tyrosine phosphorylation’s level of NMDA receptors subunits (NR2A) that reflects up-regulation of NMDA receptors activities (Wang et al., 2009).

6.6. Possible interventions on protein kinase C

The data from the previous research suggested that some mechanisms such as cell survival or death and signal transduction pathways contribute to the TCM (Traditional Chinese Medicine) neuroprotective functions (Lin et al., 2014). PKC signaling pathway and multifunctional cell survival genes were observed in 6-OHDA intoxicated PD (Parkinson's disease) models. Later treated neuroprotective TCM (Traditional Chinese Medicine) with anti-oxidative properties. It showed that treatment with neuroprotective TCM decreases cell lines (SH-SY5Y) deaths exposed by 6-OHDA (Tian et al., 2007). TCM brings back the depletion of PKC and extracellular signal-regulated kinases activities by 6- OHDA toxicity. The neuroprotective effects were eliminated by PKC inhibitors (Menard et al., 2013). Gene expression analysis indicated that TCM stopped the decrement of apoptosis signals like Mdm2 mRNAs and BAX and further increased the anti-apoptosis signals Bcl-w, Bcl-2, and Bcl-x mRNAs prompted via 6-OHDA intoxication (Moghadam et al., 2018). It showed that the dose-dependently effect of TCM was observed in the modulation of cell survival or cell death-related pathways. Early and late molecular events in neurodegeneration and the protective role of TCM with anti-oxidative properties were reviewed in MPTP PD (Parkinson's disease) models (Bian et al., 2020).

7. Conclusion and future perspective

7.1. Conclusion

The neuroprotective TCM (Traditional Chinese Medicine) studies presented in this review article encourage the researchers to think about TCM and its components against neurological disorders. Further, our review motivated future scientists to research the novel TCM extract and its components against neurodegenerative disorders mentioned in Table 1. We have written enough about neuroprotective TCM and its antioxidative properties. There is not even a single doubt about the neuroprotective capability of any drug extracts or their components mentioned in Table 1. At the same time, the effects of neuroprotective TCM and its components on various neurological models should also be discussed in future studies. For example, in pharmacogenomics, the exact role of neuroprotective TCM (Traditional Chinese Medicine) extracts and their components should also be addressed at a large scale. TCM components are playing an active role in improving intra body immunity, promoting neurogenesis, eliminating neurotoxic proteins, and repairing neural injury at the SNPc region of the brain via anti-apoptotic, anti-inflammatory, and anti-oxidative pathways, discussed above. Here we want to highlight that TCM belongs to the logical discussion in the scientific medication system, which is considered the universal concepts and syndrome differences (Du et al., 2020a,b). The use of Chinese herbs or Chinese medicine formulas is complicated without the guidance of TCM theory.

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7.2. Future perspectives

TCM (Traditional Chinese Medicine) has multi-target in actions, rather than a single effect in pathological and physiological conditions with several preventative and repairing treatment strategies, entirely different from the western medical system. Due to narrow space or lack of awareness, only a few kinds of literature were reported yet, each published in international Journals mainly by Chinese researchers in recent years. Still, it is gaining the interest of study at the international level by international scholars from the last few decades of research on mechanisms of actions of TCM (Traditional Chinese Medicine) components based on long-term clinical effectiveness. Among them, a few dynamic components are chosen, which are the natural products extracted from TCM. It has a defined structure with chemical formula

and proved helpful in anti-oxidative activity in the human body, especially against neurological disorders for many years Table 1. These TCM (Traditional Chinese Medicine) components with anti-oxidative abilities are entirely dissimilar from the artificial compounds obtained by high-throughput screening. So it is assumed that the effects of TCM endorsing neural regenerations in PD (Parkinson's disease) at the cellular level need further support to involve TCM (Traditional Chinese Medicine) studies in the research, scientifically and significantly at clinical approaches. However, several challenges to overcome before natural molecules from TCM (Traditional Chinese Medicine) could serve as a neuroprotective and alternative medicine for PD (Parkinson's disease). TCM behavioral effects on post-transcriptional modifications are needed to be discovered in future studies. Several questions still needed to be answered about finding an effective drug against PD, for instance; How to competently screen out the candidates’ medicines that can be used for neuroprotective treatments against PD (Parkinson's disease) from the vast numbers of available TCM (Traditional Chinese Medicine)? What are the in vitro and in vivo targets of the natural molecules from TCM? How to encourage the molecules to pass through the extracellular membrane and blood-brain barrier (BBB) to directly reduce the α-Syn toxicity or protect the DA neurons in the SNPs of the brain? It is promising, but a lot of work needs to be done to discover natural components ultimately. Later, be accepted as neuroprotective and implemented in the treatment of PD (Parkinson's disease) patients worldwide.

Declaration of competing interest

All authors declare they have no actual or potential competing interests.

Acknowledgments

We sincerely thank the Natural Science Foundation of Gansu Province, China, 20JR10RA596, 20JR10RA756, and the Talent innovation and entrepreneurship project of Lanzhou City, 2020-RC-43 for the grant and support in this study, especially to Dr. Liu, Yan help in writing and carefully modifying.

From: " Antioxidative role of Traditional Chinese Medicine in Parkinson's disease" by Fahim Muhammad, et al

---Journal of Ethnopharmacology 285 (2022) 114821