Recent Advances in Herbal Medicines Treating Parkinson's Disease

Contact: Audrey Hu Whatsapp/hp: 0086 13880143964 Email: audrey.hu@wecistanche.com

Xu-Zhao Li a, Shuai-nan Zhang b, Shu-min Liu a,⁎, Fang Lu a,⁎⁎

* Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin 150040, PR China

* Heilongjiang Academy of TCM, Harbin 150036, PR China

Abstract

Herbal medicines have attracted considerable attention in recent years, which are used to treat Parkinson's disease (PD) in China based on traditional Chinese medicine or modern pharmaco- logical theories. We summarized and analyzed the anti-Parkinsonian activities of herbal medicines and herbal formulations investigated in Parkinson's disease models and provide future references for basic and clinical investigations. All the herbal medicines and herbal formulations were tested on PD models in vitro and in vivo. The relevant compounds and herbal extracts with anti-Parkinsonian activities were included and analyzed according to their genera or pharmacological activities. A total of 38 herbal medicines and 11 herbal formulations were analyzed. The relevant compounds, herbal extracts, and formulations were reported to be effective on Parkinson's disease models by modulating multiple key events or signaling pathways implicated in the pathogenesis of PD. The plant species of these herbal medicines belong to 24 genera and 18 families, such as Acanthopanax, Alpinia and Astragalus, etc. These herbal medicines can be an alternative and valuable source for anti-Parkinsonian drug discovery. The plant species in these genera and families may be the most promising candidates for further investigation and deserve further consideration in clinical trials. Active components in some of the herbal extracts and the compatibility law of herbal formulations remain to be further investigated.

Keywords: Parkinson's disease, Herbal medicines, Herbal formulation, Genera

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1. Introduction

Parkinson's disease is a chronic neurological disorder. In the ventral midbrain, particularly in substantia nigra pathological features show that dopaminergic neurons progressively degenerate, which causes a consequent reduction of dopamine (DA) levels in the striatum. The functions of acetylcholine neurons and dopaminergic neurons in the striatum are out of balance, which leads to Parkinson's disease. The patients have some characteristic symptoms, such as tremor, myotonia, dyskinesia, etc. [1]. The three main strategic developments that have led to progress in the medical management of Parkinson's disease have focused on improvements in dopaminergic therapies, the identification of non-dopaminergic drugs for symptomatic improvement, and the discovery of compounds to modify the course of PD [2].

The earliest description of Parkinson's disease was traced in the Yellow Emperor's Internal Classic, a book written 2000 years ago. In traditional Chinese medicine, PD is termed as “shaking palsy”, a syndrome characterized by tremors, numbness, limpness, and weakness of the four limbs, and the pathologic features of PD are liver-kidney Yin deficiency and qi–blood deficiency [3,4]. There are abundant plant resources in China. More than 146,900 plant species have been discovered around the country, more than 22,500 of which are medicinal plants [5]. Quite a few herbal medicines and herbal formulations were used to treat PD, which were investigated in animal experiments or clinical trials. Up to now, the etiology and pathogenesis of Parkinson's disease are not fully elucidated. Although no model to date has been able to recapitulate all the pathological features of Parkinson's disease, the preclinical models of study of Parkinson's disease (biochemical, cellular, and animal) have contributed much to our understanding of Parkinson's disease in humans. Three neurotoxins, 6-hydroxydopamine (6-OHDA), 1-methyl- 4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP), and rotenone, are the most successful agents so far to mimic Parkinson's disease in vitro and in vivo. 6-OHDA is taken up by the dopamine transporter and generates free radicals. MPTP is converted by monoamine oxidase B into MPP+ and then taken up by the dopamine transporter and can be accumulated by mitochondria, leading to complex I inhibition and the generation of free radicals. Rotenone is a direct inhibitor of complex I, which also leads to free radical generation [6]. C57/BL6 mice, Wistar rat, PC12 cells, and SH-SY5Y cells could serve as valuable tools for the assessment of efficacy and side-effects of symptomatic treatments of Parkinson's disease in vivo or in vitro, respectively. Extensive study of these models has defined important cellular actors of cell death including oxidative stress, mitochondrial dysfunction, excitotoxicity, neuroinflammation nitric oxide, etc. [7,8].

In recent years, increasing interest has been devoted to the treatment or prevention of Parkinson's disease by herbal medicines. Recent studies have indicated that a part of active compounds extracted from herbal medicines, herbal extracts, and herbal formulations have effects on Parkinson's disease models in vitro and in vivo. A total of 38 herbal medicines and 11 herbal formulations were included in this review, the aim of which is to systematically summarize and analyze the herbal medicines investigated in PD models and provide future references for basic and clinical investigations.

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2. Herbal extracts and active components with anti- Parkinsonian activities

The herbal medicines were listed in Table 1, which have been shown to be effective on Parkinson's disease models according to their genera. The molecular structures of active components were identified and shown in Fig. 1.

2.1. Acanthopanax

Acanthopanacis Senticosi Radix Et Rhizoma Seu Caulis is the dried roots and rhizomes of Acanthopanax senticosus (Rupr. et Maxim.) Harms. (Araliaceae), 80% ethanol extract which has protective effects on dopaminergic neurons in Parkinson's disease mice model induced by MPTP-HCl [1]. The stem bark of A. senticosus Harms is also effective on Parkinson's disease model in vivo, 100% ethanol, 50% ethanol, and hot water mixed extract of which can be a prophylactic for MPTP-induced PD in rats, and increase the level of DA and noradrenaline (NA) in a Parkinson's disease rat model [9,10]. The components of A. senticosus Harms contain sesamin and eleutheroside B, etc. Sesamin has a preventive effect on behavioral dysfunction in rotenone-induced rats [11]. Sesamin modulates tyrosine hydroxylase (TH), superoxide dismutase, catalase (CAT), inducible nitric oxide synthase (iNOS), and interleukin-6 expression in dopaminergic cells under MPP+-induced oxidative stress [12]. Eleutheroside B can increase extracellular regulated protein kinases 1/2 phosphorylation and reduce c-fos and c-jun expressions in MPP+-induced PC12 cells [13].

2.2. Alpinia

Alpinia Oxyphyllae Fructus is the dried, ripe seed of Alpinia oxyphylla Miq. (Zingiberaceae), 80% ethanol extract which can protect against 6-OHDA-induced damage of PC12 cells and dopaminergic neurons in zebrafish [14]. Protocatechuic acid derived from A. oxyphylla has effects on the Parkinson's disease model in vitro and in vivo. Protocatechuic acid inhibits neurotoxicity induced by MPTP in mice [15]. In vitro, protocatechuic acid can inhibit rat pheochromocytoma cell damage induced by a dopaminergic neurotoxin [16], suppress mitochondrial dysfunction and apoptotic cell death [17], and enhance the activities of reactive oxygen species (ROS) and CAT in MPP+-induced PC12 cells [18]. In addition, protocatechuic acid also dose-dependently reduces the hydrogen peroxide (H2O2)- or sodium nitroprusside- induced cell death in PC12 cells [18].

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2.3. Astragalus

Astragali Radix is the dried root of Astragalus membranaceus (Fisch.) Bge. var. Mongolians (Bge.) Hsiao or Astragalus membranaceus (Fisch.) Bge. (Leguminosae). Astragaloside IV and Astragalus polysaccharides are extracted from Astragali Radix. Astragaloside IV prevents MPP+-induced SH-SY5Y cell death via the inhibition of Bax-mediated pathways and ROS production [19]. Astragaloside IV pretreatment significantly and dose-dependently attenuates 6-OHDA-induced loss of dopaminergic neurons and increases the level of TH and iNOS immunoreactivities in 6-OHDA treated nigral cell cultures [20]. Free radical produced by self-oxidation of bendopa can promote the development of Parkinson's disease. Astragalus polysaccharides can relieve the toxicity of bendopa on neurons and the effect has time-dependency [21].

2.4. Camellia

Green tea is the product derived from the leaves of Camellia sinensis (L.) O. Kuntze (Theaceae). A recent study indicated that the intake of Chinese and Japanese teas can reduce the risk of PD, such as oolong tea green tea, etc. [22]. Green tea extracts can attenuate 6-OHDA-induced nuclear factor-κB (NF-κB) activation and cell death in SH-SY5Y cells [23]. Polyphenolic catechins derived from green tea have protective effects on the SH-SY5Y cells and the rat model of PD through inhibition of ROS–nitrogen monoxide (NO) pathway [24,25]. The four main components of polyphenolic

catechins are (−)-epigallocatechin-3-gallate, (−)-epicatechin gallate, (−)-epigallocatechin, and (−)-epicatechin. The classified protective effects of the four catechins on PC12 cells are in the order (−)-epicatechin gallate>(−)-epigallocatechin-3- gallate>(−)-epicatechin >(−)-epigallocatechin [26]. (−)- Epigallocatechin-3-gallate can regulate dopamine transporter

internalization via protein kinase C-dependent pathway in MPP+-induced PC12 cells [27], reducing dichloro diphenyl- trichloroethane-induced cell death in dopaminergic SHSY-5Y cells [28]. In vitro, (−)-epigallocatechin-3-gallate can inhibit iNOS expression and cell death in the MPTP mice of Parkinson's disease [29,30].

2.5. Cassia

Cassiae Semen is the dried, ripe seed of Cassia obtusifolia L. or Cassia tora L. (Leguminosae), 85% ethanol extract of which has effects against neurotoxicities induced by 6-OHDA in PC12 cells, and significantly protects DA neuronal degeneration induced by MPTP in the mouse Parkinson's disease model [31]. Peroxynitrite (ONOO)-toxicity is also reported to be involved in inflammatory and neurodegenerative diseases such as PD, and later in isolated from C. Tora has potent ONOO-scavenging and anti-inflammatory activities, which would be a candidate for Parkinson's disease [32,33].

2.6. Chrysanthemum

Chrysanthemi Flos is the dried flowering head of Chrysanthemum morifolium Ramat. (Asteraceae), and Chrysanthemi Indici Flos is the dried flowering head of Chrysanthemum Indicum L. (Asteraceae). The water extract of C. morifolium Ramat. can inhibit cytotoxicity and improve cell viability in MPP+-induced SH-SY5Y cells [34]. Methanol extract of C. Indicum L. has effects against MPP+-induced damage in SH-SY5Y cells and lipopolysaccharide (LPS)-stimulated BV-2 microglial cells [35].

2.7. Cistanche

Cistanches Herba is the dried succulent stem of Cistanche deserticola Y. C. Ma or Cistanche tubulosa (Schrenk) Wight (Orobanchaceae). Cistanche total glycosides derived from Cistanches Herba have protective effects on dopaminergic neurons in substantia nigra of MPTP-induced PD mice model [36]. Echinacoside, a phenylethanoid glycoside isolated and purified from the stems of another plant species in this genus (Cistanche salsa) prevents the striatal extracellular levels of monoamine neurotransmitters from diminution in 6-OHDA lesion rats [37], and has neuroprotective, neurotrophic, and neurorescue effects on the mouse MPTP model of Parkinson's disease [38,39]. Acteoside extracted from Cistanches Herba has neuroprotective effects against rotenone-induced damage of SH-SY5Y cells or MPTP-induced mouse model of Parkinson's disease [40,41].2.8. Cuscuta Cuscutae Semen is the dried, ripe seed of Cuscuta australis R. Br. or Cuscuta Chinensis Lam. (Convolvulaceae), methanol extract of which can protect cells from apoptosis induced by MPP+ in PC12 cells [42].

2.8. Cuscuta Cuscutae

Semen is the dried, ripe seed of Cuscuta australis R. Br. or Cuscuta Chinensis Lam. (Convolvulaceae), methanol extract of which can protect cells from apoptosis induced by MPP+ in PC12 cells [42].

2.9. Fraxinus

Fraxini Cortex is the dried tegument of Fraxinus rhynchophylla Hance, Fraxinus Chinensis Roxb., Fraxinus szaboana Lingelsh. or Fraxinus stylosa Lingelsh. Fraxetin derived from Fraxini Cortex has effects on antioxidant defense and stress proteins, and may prevent the apoptotic death of dopaminergic cells induced by rotenone and mediated by oxidative stress in SH-SY5Y cells [43–46]. Esculin, 6,7-di-O-glucopyranosyl-esculetin, and liriodendron are extracted from another plant species in this genus (Fraxinus sielboldiana Blume). Esculin has anti-apoptotic effects on MPP+- or DA-induced cytotoxicity in SH-SY5Y cells [47,48]. 6,7-Di-O-glucopyranosyl-esculetin and liriodendron can protect SH-SY5Y cells from DA-induced cytotoxicity [49,50].

2.10. Gastrodia

Gastrodiae Rhizoma is the dried tuber of Gastrodia elata Bl. (Orchidaceae), 95% ethanol extract has protective effects on MPP+-induced cytotoxicity in human dopaminergic SH-SY5Y cells [51]. Vanillyl alcohol, a major bioactive component of Gastrodiae Rhizoma, protects dopaminergic MN9D cells against MPP+-induced apoptosis by relieving oxidative stress and modulating the apoptotic process and is, therefore, a potential candidate for the treatment of neurodegenerative diseases such as Parkinson's disease [52].

2.11. Ginkgo

Ginkgo Folium is the dried whole leaf of Ginkgo biloba L. (Ginkgoaceae). A multicenter observational study in a German network of complementary and alternative medicine physicians indicated that dementia was classified as unspecified dementia (57.2%), vascular dementia (25.1%), dementia in Alzheimer's disease (10.4%), and dementia in Parkinson's disease (7.3%), and G. Biloba is the most frequently prescribed anti-dementia drug overall (67.6% of all) [53]. G. Biloba extract 761 has protective effects on paraquat-induced apoptosis of PC12 cells [54], has neuroprotective effects on the 6-OHDA-induced rat model of Parkinson's disease [55], and has an inhibitory effect against oxidative stress, regulates copper homeostasis in the brain, and attenuates MPTP-induced neurodegeneration of the nigrostriatal pathway in Parkinson's disease mice model [56,57].

2.12. Gynostemma

Five leaf Gynostemma Herb is the dried whole herb of Gynostemma pentaphyllum (Thunb.) Makino (Cucurbitaceae), herbal ethanol extracts from which have neuroprotective effects on the 6-OHDA-lesioned rat model of Parkinson's disease [58]. Gypenosides, the saponins extract derived from the G. pentaphyllum, can protect dopaminergic neurons in primary culture or in the substantia nigra of a mouse model of Parkinson's disease against MPP+-induced oxidative injury [59,60].

2.13. Hypericum

Hypericin Perforati Herba is the dried aerial part of Hypericum perforatum L. (Guttiferae), methanol extract of which has a neuromodulating effect against MPTP-induced Parkinson's disease in mice [61]. The standard extracts of H. perforatum L. have neuroprotective effects on trauma-induced by H2O2 in PC12 cells [62], reduce oxidative stress, and increase gene expression of antioxidant enzymes on rotenone-exposed rats [63]. A flavonoid-rich extract of H. perforatum L. has protective effects against H2O2- induced apoptosis in PC12 cells [64]. Hyperoside isolated from H. perforatum L. has protective effects against cytotoxicity induced by H2O2 and tert-butyl hydroperoxide in PC12 cells [65]

2.14. Ligusticum

Chuanxiong Rhizoma is the dried rhizome of Ligusticum chuanxiong Hort. (Umbelliferae). Tetramethylpyrazine, an active component derived from Chuanxiong Rhizoma, can improve the DA metabolic ratio in the striatum and reduce the oxidative damage in Parkinson's disease rats induced by levodopa [66,67]. Tetramethylpyrazine also has neuroprotective effects against MPTP-induced dopaminergic neurotoxicity in a mouse model of Parkinson's disease [68,69].

2.15. Paeonia

Paeoniae Radix Alba is the dried root of Paeonia lactiflora Pall. (Ranunculaceae). Paeoniflorin is the principal bioactive component of Paeoniae Radix Alba, which is widely used in Traditional Chinese Medicine for the treatment of neurodegenerative disorders such as Parkinson's disease. Paeoniflorin can protect PC12 cells from MPP+ and acidic damage via autophagic pathway [70], alleviate the neurological impairment following unilateral striatal 6-OHDA lesion in a rat model [71], and attenuate neuroinflammation and dopaminergic neurodegeneration in the mouse model of Parkinson's disease by activation of adenosine A1 receptor [72].

2.16. Panax

Ginseng Radix Et Rhizoma is the dried root and rhizoma of Panax ginseng C. A. Mey. (Araliaceae), water extract of which has protective effects on MPP+-induced apoptosis in SH-SY5Y cells [73]. Ginseng extract G115 has neuroprotective actions against the MPTP-induced mice model or MPP+-induced rat model of Parkinson's disease [74]. Among more than 30 ginsenosides, the active ingredients of ginseng, ginsenosides Rb1, Rd, Re, and Rg1 are regarded as the main compounds responsible for many pharmaceutical actions of ginseng. Ginsenoside Rb1 has a partial neurotrophic and neuroprotective role in dopaminergic cell culture [75]. Ginsenoside Rd attenuates neuroinflammation of dopaminergic cells in culture [76]. Ginsenoside Re has protective effects against MPTP-induced apoptosis in substantia nigra neurons of the PD mouse model [77]. In vitro, ginsenoside Rg1 has effects on mesencephalic dopaminergic cells stressed with glutamate [75], attenuates DA-induced apoptosis by suppressing oxidative stress and protects against H2O2-induced cell death via inhibiting NF-κB activation in PC12 cells [78,79], protects iron-induced neurotoxicity through antioxidant and iron regulatory proteins in 6-OHDA-treated MES23.5 cells [80], and protects the MPP+-treated MES23.5 cells via attenuating divalent metal transporter 1 up-regulation and cellular iron uptake [81]. In the mice model, ginsenoside Rg1 has protective effects on MPTP-induced apoptosis in substantia nigra neurons [82,83], reduces nigral iron levels by regulating certain iron transport proteins [84], and has an inhibitory effect on LPS-induced microglial activation [85]. In a rat model, ginsenoside Rg1 has protective effects on dopaminergic neurons in the ovariectomized rat model of PD or in the 6-OHDA-induced rat model through the insulin-like growth factor-I receptor signaling pathway [86,87] and has neuroprotective effects against rotenone toxicity [88]

Notoginseng Radix Et Rhizoma is the dried root and rhizoma of Panax notoginseng (Burk.) F. H. Chen (Araliaceae), the ethanol extracts of which can inhibit toll-like receptor-ligand- and interferon gamma-induced activation in N9 and EOC20 microglial cell lines, and maybe a therapeutic benefit in treating or preventing neurodegenerative diseases such as Parkinson's disease [89]. Panaxatriol saponins extracted from P. notoginseng can induce thioredoxin-1 and prevent MPTP-induced neurotoxicity in vivo and in vitro [90,91]. Notoginsenoside-Rg1 also extracted from P. notoginseng may repress the immune inflammation response and regulate the immune function through the neuro-immune molecular network and has antagonistic effects on immunoinflammatory injury in the rat model of Parkinson's disease [92,93].

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2.17. Polygala

Polygala Radix is the dried root of Polygala tenuifolia Willd. or Polygala sibirica L. (Polygalaceae), the water extract of which can inhibit toxin-induced neuronal death in the PC12 cell induced by MPP+ [94]. Tenuigenin derived from P. tenuifolia has neuroprotective effects against 6-OHDA-induced injury in an SH-SY5Y cell [95], and protects dopaminergic neurons from inflammation-mediated damage induced by the LPS [96].

2.18. Polygonum

Polygoni Cuspidati Rhizoma Et Radix is the dried root and rhizoma of Polygonum cuspidatum Sieb. et Zucc. (Polygonaceae). In vitro, resveratrol derived from P. cuspidatum induces autophagy to prevent human prion protein-mediated neurotoxicity, to protect against rotenone-induced apoptosis in SH-SY5Y cells, and to enhance degradation of α-synucleins in α-synuclein-expressing PC12 cell lines and also has protective effects against MPP+-induced oxidative stress act by modulating markers of apoptotic death in dopaminergic neurons [97–99]. In primary cultures of cerebellar granule neurons, the antiapoptotic effects of resveratrol in MPP+ are independent of the stimulation of mammalian silent information regulator 2 and depend on its antioxidant properties [100]. In organotypic midbrain slice cultures, resveratrol protects dopaminergic neurons from multiple insults [101]. In the mice models, resveratrol has neuroprotective effects on MPTP-induced neuron loss mediated by free radical scavenging [102], potentiates cytochrome P450 2 d22-mediated neuroprotection in maneb- and paraquat-induced parkinsonism [103]. Resveratrol has neuroprotective effects on nigral cells and attenuates oxidative damage and DA depletion in the 6-OHDA-induced rat model [104–106]. Pinostilbene, a resveratrol methylated derivative, has protective effects against 6-OHDA-induced neurotoxicity in SH-SY5Y cells [107].

2.19. Psoralea

Psoralea Fructus is the dried, ripe seed of Psoralea corylifolia L. (Leguminosae), a water extract that has inhibitive effects on DA transporter and NA transporter [108]. The bakuchiol analog, Δ3,2-hydroxybakuchiol isolated from P. corylifolia L. has in vitro dopaminergic neuroprotective and in vivo antiparkinsonian-like effects and can inhibit monoamine transporters and regulate monoaminergic functions [109,110].

2.20. Pueraria

Puerariae Lobatae Radix is the dried root of Pueraria lobata (Willd.) Ohwi (Leguminosae), and Puerariae Thomsonii Radix is the dried root of Pueraria thomsonii Benth. (Leguminosae). Puerarin, an active component purified from P. lobata (Willd.) and P. thomsonii Benth., has protective effects against MPP+-elicited apoptosis in SH-SY5Y cell via activating phosphoinositide 3-kinase (PI3K)/Akt pathway and regulating the function of the ubiquitin-proteasome system [111,112], or in PC12 cells via c-Jun-NH2-terminal kinase pathway [113], and also protects dopaminergic neurons against 6-OHDA neurotoxicity via inhibiting apoptosis and upregulating glial cell line-derived neurotrophic factor in a rat model of PD [114]. Daidzein and genistein, the active constituents isolated from P. thomsonii Benth. have neurocytoma protective effects on 6- OHDA-treated nerve growth factor (NGF)-differentiated PC12 cells [115].

2.21. Rhodiola

Rhodiola Crenulatae Radix Et Rhizoma is the dried root and rhizoma of Rhodiola crenulata (Hook. f. et Thoms.) H. Ohba (Crassulaceae). Salidroside, a phenylpropanoid glycoside isolated from Rhodiola Crenulatae Radix Et Rhizoma and another plant species in this genus (Rhodiola Rosea L.), protects against MPP+-induced apoptosis in PC12 cells by inhibiting the NO pathway and activating PI3K/Akt pathway [116,117] and has effects on PI3K/protein kinase B signaling in a PD mice model as well [118].

2.22. Salvia

Salviae Miltiorrhizae Radix Et Rhizoma is the dried root and rhizoma of Salvia miltiorrhiza Bge. (Labiatae). Salvianic acid A, salvianolic acid A and salvianolic acid B were isolated from Salviae Miltiorrhizae Radix Et Rhizoma. In SH-SY5Y cells, salvianolic acid A protects against MPP+-induced cytotoxicity [119], and salvianolic acid A protects against H2O2- induced injury by increasing stress tolerance ability [120]. Salvianolic acid B protects against 6-OHDA- or MPP+- induced apoptosis in SH-SY5Y cells and H2O2-induced cytotoxicity in PC12 cells [121–123].

2.23. Scutellaria

Scutellariae Radix is the dried root of Scutellaria baicalensis Georgi (Labiatae). Baicalein, a flavonoid obtained from Scutellariae Radix, exerts neuroprotective effects in 6-OHDAinduced experimental parkinsonism in vivo and in vitro [124,125], protects against rotenone-induced neurotoxicity in PC12 cells and isolated rat brain mitochondria [126], protects HT22 murine hippocampal neuronal cells against endoplasmic reticulum stress-induced apoptosis through inhibition of ROS production and C/EBP homologous protein induction [127] and attenuates inflammation-mediated degeneration of dopaminergic neurons via inhibiting microglial activation [128]. Baicalein can inhibit the formation and fibrillation of α-synuclein, and prevent Aβ peptide fibrillation and oligomerization as well [129,130]. In the mice model, baicalein has neuroprotective effects against MPTP-induced neurotoxicity [131,132].

2.24. Tripterygium

Common Threewingnut Root is the dried root and of Tripterygium wilfordii Hook F. (Celastraceae), extract of which can protect dopaminergic neurons against LPS-induced inflammatory damage [133]. Tripchlorolide and triptolide were extracted from Common Threewingnut Root. Tripchlorolide has neurotrophic and neuroprotective effects on dopaminergic neurons [134]. Triptolide can enhance adeno associated virus-mediated gene transfer in mice striatum [135] and upregulate NGF synthesis in rat astrocyte cultures [136], protecting dopaminergic neurons against MPP+- or LPS-induced damage via inhibiting microglial activation or its immunosuppressive therapy [137–139].

In this review, 39 herbal-derived compounds were identified and analyzed, the main structure types of which belong to catechols, stilbenoids, flavonoids, phenylpropanoids, and lignans, phenylethanoid glycosides, phenolics, saponins, etc. They have anti-oxidant, anti-apoptotic and anti-inflammatory effects, etc., which are active and potentially useful for Parkinson's disease. Various herbs are composed of a variety of active compounds, and the molecular trait, pharmacological effects, and potency of the active compounds determine the mechanism of action and potency of the various herbs.

Various herbal-derived compounds have shown experimental anti-PD effects. Meanwhile, efforts have been made to decipher their mechanisms of action, either in vitro or in vivo. For drugs acting on central nervous systems, their bioavailability and the ability to penetrate the blood-brain barrier should be a prior consideration. For instance, phenolics and saponins are, in general, poorly absorbed, and either conjugated or stripped of their sugar decoration, and their blood concentrations would be deficient and the anti-oxidant effects would be weak in vivo. This would obviously be a limitation for the pre-clinical translation of cellular data, which would not reflect their effects factually in vivo and would not be suitable references for clinical studies. To improve their pharmacokinetic properties and increase the absorption could adjust their dosage, administration method modify their structures, etc. Although some active compounds have shown positive results on Parkinson's disease models, their possibility of being drugs remains to be further investigated.

Cistanche extract: Preventing Parkinson's Disease

3. Herbal formulation with anti-Parkinsonian activities (Table 2)

Ban Xia Hou Po Tang can significantly improve the swallowing reflex in Parkinson's disease patients [140]. Bushen Yanggan Xifeng Decoction has effects on neurotransmitters and DA receptors in the striatum of PD model mice [141]. Chuanxiong Chatiao pelvis has neuroprotective effects against MPTP-induced dopaminergic neurotoxicity in mice models of Parkinson's disease[142]. Huanglian Jiedu Decoction has protective effects on the injury of PC12 cells induced by MPP+ [143]. Kami-shojo-san has effects against tremors due to antipsychotic-induced PD [144]. Liuwei Dihuang Pill can protect dopaminergic neurons in MPTP-induced PD mice [145,146]. San-Huang-Xie-Xin-Tang has neuroprotective effects in the MPP+/MPTP models of PD in vitro and in vivo [147]. Tianma Gauteng Yin has protective effects against apoptosis of dopaminergic neurons and oxidation stress response in Parkinson's disease model rats [148,149]. Yeoldahansotang has neuroprotective effects on the PD model via autophagy enhancement [150]. Zhen-wu-tang has ameliorative and neuroprotective effects on rats induced by MPTP through keeping DA stable and vesicular monoamine transporter 2/DA transporter mRNA in balance [151,152]. Zeichen Soup has the effect of promoting neural stem cell differentiation in PD model rats [153,154].

4. Conclusion and future directions

There are multiple targets for treating Parkinson's disease, which is a complex syndrome. In general, single-component just acts on one or a few targets, so it is difficult to control a complex syndrome everlastingly and stably. Herbal formulations contain multiple medicines which contain multiple components, and using herbal medicines or herbal formulations would act on multiple targets and control a complex syndrome well.

There may be identical or analogous components derived from diverse plants species in one genus, which would have similar pharmacological activities. In this review, we have summarized and analyzed 38 herbal medicines in 24 genera and 18 families, which have obvious effects on Parkinson's disease models in vitro and in vivo. We can go on studying these herbal medicines or discover new medicines from these genera or even these families.

For some herbal extracts, in-depth experimental studies are still needed to find out their active components and evaluate their efficacy in Parkinson's disease models, and we would discover new active component groups with better therapeutic effects and less untoward effects.

For herbal formulations, in-depth experimental studies are still needed to summarize their compatibility law and find out the indispensable medicines and their optimum dosage. The optimum compatibility law contains 5 points: (1) acting on multiple targets; (2) enhancing effects on each target; (3) avoiding adverse interaction within medicines; (4) taking effects everlastingly and stably and avoiding tolerance; and (5) working out reasonable dosage range. We would discover new herbal formulations in the optimum compatibility law, which can treat complex syndromes including Parkinson's disease.

Acknowledgments

This article is supported by the National Natural Science Foundation of China (81073019 and 81270056) and the National Natural Science Foundation of Youth Science Fund (30901974).

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