Recent advances in discovery and development of natural products as source for anti-Parkinson's disease lead compounds

European Journal of Medicinal Chemistry Volume 141, 1 December 2017, Pages 257-272 European Journal of Medicinal Chemistry Review article Author links open overlay panelHongjiaZhanga1LanBaia1JunHebLeiZhongaXingmeiDuanaLiangOuyangbYuxuanZhuaTingWangaYiwenZhangbJianyouShia a Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu 610072, China b State Key Laboratory of Biotherapy & Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center of Biotherapy, Chengdu 610041, China Received 12 July 2017, Revised 25 August 2017, Accepted 29 September 2017, Available online 30 September 2017. crossmark-logo https://doi.org/10.1016/j.ejmech.2017.09.068 Get rights and content Highlights • Many natural products exhibit anti-PD efficacy in vivo or vitro. • Many natural products possess good anti-oxidative and anti-inflammatory effects as well as suppressing protein misfolding. • The anti-PD properties of some natural products are closely related to PD related molecular signaling pathways. • Detailed investigations into the structure–activity relationships of natural products may guide the design of anti-PD drugs. Abstract Parkinson's disease (PD) is a common chronic degenerative disease of the central nervous system. Although the cause remains unknown, several pathological processes and central factors such as oxidative stress, mitochondrial injury, inflammatory reactions, abnormal deposition of α-synuclein, and cell apoptosis have been reported. Currently, anti-PD drugs are classified into two major groups: drugs that affect dopaminergic neurons and anti-cholinergic drugs. Unfortunately, the existing conventional strategies against PD are with numerous side effects, and cannot fundamentally improve the degenerative process of dopaminergic neurons. Therefore, novel therapeutic approaches which have a novel structure, high efficiency, and fewer side effects are needed. For many years, natural products have provided an efficient resource for the discovery of potential therapeutic agents. Among them, many natural products possess anti-PD properties as a result of not only their wellrecognized anti-oxidative and anti-inflammatory activities but also their inhibitory roles regarding protein misfolding and the regulatory effects of PD related pathways. Indeed, with the steady improvement in the technologies for the isolation and purification of natural products and the in-depth studies on the pathogenic mechanisms of PD, many monomer components of natural products that have anti-PD effects have been gradually discovered. In this article, we reviewed the research status of 37 natural products that have been discovered to have significant anti-PD effects as well as their mode of action. Overall, this review may guide the design of novel therapeutic drugs in PD. Graphical abstract Image 1 Download high-res image (244KB)Download full-size image Previous article Next article Keywords Parkinson's disease Natural products Mode of action Signalling pathway 1. Introduction Parkinson's disease (PD), also known as idiopathic paralysis agitans, is a common chronic degenerative disease of the central nervous system. The major clinical symptoms of PD are muscle tremor, rigidity, dyskinesias, and imbalances in body posture and movement. In severe cases, daily activities including eating and dressing are also affected. The pathological features of patients with PD are degeneration of dopaminergic neurons of the substantia nigra pars compacta and a significant reduction in the level of transmitters in dopaminergic neurons in the striatum. As a result, the function of nigrostriatal dopaminergic neurons is low, while the function of cholinergic neurons becomes relatively dominant, which causes the development of movement disorders [1-3]. Current hypotheses of the pathogenic mechanisms of PD include oxidative stress, mitochondrial injury, excitatory amino acid toxicity, ubiquitin proteasome system damage, proteolytic stress, immune disorders, inflammatory reactions, dopamine transporter (DAT) inactivation, abnormal deposition of α-synuclein, and cell apoptosis. However, the pathogenic factors that are present in the majority of PD patients have not been confirmed. Most of the current viewpoints consider that fibrillation and the abnormal aggregation of α-synuclein are the key factors in the cascade of PD pathological events. α-synuclein is a soluble protein presynaptically expressed in central nervous system, and it can abnormally express or aggregate when affected by various factors. In these biochemical processes, many factors such as oxidative stress and intermediate conformation of oligomers, play important roles in the pathogenesis of PD. In addition, an important pathological hallmark of Parkinson's disease is the presence of Lewy bodies (LBs) that is composed of α-Syn. Therefore, α-Syn may has a close relation with Parkinson disease(PD) [4-6]. Furthermore, with the recent and rapid development of technologies in the life sciences and the continuous in-depth studies on proteomics and molecular biology, an increasing amount of evidence indicates that many typical molecular signalling pathways are closely associated with the development and progression of PD. These pathways mainly include the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signalling pathway [7,8], the nuclear factor erythriod2-related factor2 (Nrf2) signalling pathway [9,10], the P38 mitogen-activated protein kinase (P38MAPK) signalling pathway [11,12], the glycogen synthase kinase-3β (GSK-3β) signalling pathway [13-15], the c-jun-N-terminal kinase (JNK) signalling pathway [16,17], the nuclear transcription factor-κB (NF-κB) signalling pathway [18,19], the Wnt signalling pathway [20,21], and the autophagy-lysosome pathway (ALP) [22,23]. PD primarily occurs in middle-aged and elderly individuals. It has been reported that the incidence of PD in the population over the age of 65 is as high as 1/200 and that PD has become one of the most common neurodegenerative diseases among middle-aged and elderly people [24]. As the issue of ageing in the population becomes increasingly prominent, the incidence of PD will gradually increase, and it will definitely become one of the major diseases that threatens human health in future societies. Currently, anti-PD drugs are classified into two major groups: drugs that affect dopaminergic neurons and anti-cholinergic drugs. The representative drug that affects dopaminergic neurons is l-DOPA. It is still the clinically preferred drug for PD treatment. This drug is primarily catalysed by dopa decarboxylase in the brain, at which point it is converted into dopamine; this supplements the dopamine deficiency and produces therapeutic effects. The representative anti-cholinergic drug, trihexyphenidyl, can block striatal cholinergic receptors and inhibit the excitability of cholinergic nerves; in addition, it can also inhibit dopamine re-uptake in the synaptic cleft to enhance the function of dopaminergic neurons, which leads to anti-paralysis agitans effects. However, during the induction of these therapeutic effects, the two most common anti-PD drugs discussed above also produce severe adverse reactions such as an increase in transaminases and extrapyramidal reactions. Consequently, these drugs cannot fundamentally improve the degenerative process of dopaminergic neurons; thus, their clinical applications are always limited [25-27]. Therefore, the search for anti-PD compounds that have a novel structure, high efficiency, and fewer side effects has become an important research direction in the field of neurodegenerative diseases. In recent years, researchers have conducted the in-depth studies on the pathogenic mechanisms of PD and its clinical manifestations in patients, leading to the discovery of several novel anti-PD targets and compounds for them, such as the angiotensin-converting enzymes inhibitors(perindopril and fosinopril) [28,29], the microtubule-stabilizing agents(GS-164 and CID4970947) [30,31], the phospholipase A2 (PLA2) inhibitors (Varespladib and LY311727) [32,33], the erythropoietin (EPO) receptor agonists (A5B10C8 and Eltrombooag) [34,35], the L-type calcium channel blockers (S-312d and Verapamil) [36,37] and so on. At present, the search for leading compounds in natural products that have therapeutic functions and the further optimization of their structures have become important routes in modern medicinal chemistry research. So, with the steady improvement in the technologies used in the isolation and purification of monomer components of natural products, specific individual ingredients of natural products have been drawing attention as PD treatments due to their excellent efficacy. This article reviewed recently discovered natural products that have significant anti-PD properties and the status of the research with respect to their medicinal chemistry. 2. Natural anti-PD products For many years, natural products have provided an efficient resource for the discovery of potential therapeutic agents. Among them, many natural products possess anti-PD properties as a result of not only their wellrecognized anti-oxidative and anti-inflammatory activities but also their inhibitory roles regarding iron accumulation, protein misfolding and the maintenance of proteasomal degradation, as well as mitochondrial homeostasis [38]. Further more, Some natural products can exert anti PD effects by affecting different pathogenic pathways of Parkinson's disease [39]. So, with the steady improvement in the technologies used in the isolation and purification of monomer components of natural products, the in-depth studies on the pathogenic mechanisms of PD, and the clinical manifestations in PD patients in recent years, more and more monomer components of natural products that have anti-PD effects have also been gradually elucidated (see Table 1). Table 1. Description of the 37 monomer components of natural products used in this review. Name of compound Class/description Sources Mode of Action Reference Baicalein Flavonoid Scutellaria baicalensis Antioxidant, Anti-inflammatory, α-synuclein fibrils↓ [40-44] Quercetin Flavonoid Red/yellow onions,wine, apples, cranberries Antioxidant enzymes↑, Anti-inflammatory, α-synuclein fibrillation↓ [45-47] Puerarin Flavonoid Pueraria mirifica TH-positive neurons↑, JNK↓, PI3K/Akt↑ [48-50] Daidzein Flavonoid Pueraria mirifica caspase-8 activity↓, caspase-3 activity↓ [51] Genistein Flavonoid Pueraria mirifica caspase-8 activity↓, caspase-3 activity↓ [51] Hyperoside Flavonoid Hypericaceae and Rosaceae plants antioxidant [52] Naringin Flavonoid tomatoes, grapefruits, and many other citrus fruits Antioxidant, anti-inflammatory, anti-apoptotic [53,54] Curcumin Flavonoid turmeric oxygen species levels↓, cytochrome c release↓, caspase-9 and caspase-3 activity↓, aggregation of α-synuclein↓ [55,56] Epigallocatechin gallate(EGCG) Polyphenol green tea Fibrillogenesis↓(α-synuclein and amyloid-β), aggregation of α-synuclein↓ [57,58] Resveratrol Polyphenol skin of grapes, blueberries, peanut a-synuclein expression and aggregates↓ [59,60] Danshensu Phenylpropanoid Salvia miltiorrhiza antioxidant, anti-apoptotic [61] Salvianolic acid B Phenylpropanoid Salvia miltiorrhiza caspase-3 activity↓, oxidative stress↓ [62,63] Eleutheroside B Phenylpropanoid Eleutherococcus senticosus phosphorylation level of ERK1/2 proteins↑ [64] Magnolol Phenylpropanoid Magnolia officinalis DA↑,TH↓ [65-67] Fraxetin Phenylpropanoid Fraxinus bungeana reduced glutathione↑, lipid peroxidation reactions↓ [68] Esculin Phenylpropanoid Aesculus hippocastanumlinn reactive oxygen species↓, caspase-3 activity↓, apoptosis-inducing factors↓ [69] Umbelliferone Coumarin fruits, vegetables, and herbs anti-oxidant, free radical scavenging, GSH↑, apoptosis↓ [70,71] 2-methoxy-6-acetyl-7-methyljuglone (MAM) Quinone Fallopia japonica anti-apoptotic, phosphorylation of ERK1/2, JNK, and p38MAPK↓ [72] Thymoquinone Quinone Nigella sativa anti-oxidant, anti-inflammatory, synaptic activity↓ [73-76] Alaternin Quinone cassia seeds Antioxidant, iNOS↓ [77,78] Astragaloside Triterpenoid saponins Astragalus NOS↑, reactive oxygen species↓, Bax/Bcl-2 ratio↓, caspase-3 activity↓ [79,80] Ginsenoside Rb1 Steroidal saponins ginseng LDH↑, DA↑, α-syn fibrillation↓ [81,82] Ginsenoside Rd Steroidal saponins ginseng anti-inflammatory [83] Ginsenoside Re Steroidal saponins ginseng iNOS↓, caspase-3 activity↓Bax/Bcl-2 ratio↓ [84] Ginsenoside Rg1 Steroidal saponins ginseng Antioxidant, NF-κB/p65↓, activity of Akt and ERK1/2↓ [85] Notoginsenoside Rg1 Steroidal saponins Panax notoginseng c-Fos↓, GFAP↓, GDNF↓, NF-KB↓, TNF-α↓, and IL-lp↓ [86] Panaxatriol saponin Steroidal saponins Panax notoginseng TRX-1↑ [87] Ligustrazine Alkaloid Ligusticum striatum SOD↑,GSH↑, anti-inflammatory, antioxidant, anti-apoptotic, Bax/Bcl-2 ratio↓ [88,89] Nicotine Alkaloid Solanaceae plant calcium ion concentration↓, α-synuclein fibrillation↓ [90-93] Isorhynchophylline (IsoRhy) Alkaloid Uncaria rhynchophylla. α-syn monomers↓, α-syn oligomers↓,α-syn/synphilin-1 aggregates↓ [94] l-stepholidine Alkaloid Stephania japonica antagonize D2-like receptor, stimulate the 5-HT1A receptor [95] Triptolide Terpenoid Tripterygium wilfordii anti-inflammatory [96-98] Ginkgolide B Terpenoid ginkgo biloba caspase-3 activity↓, Calbindin D28k mRNA↑, calcium ion concentration↓ [99] Catalpol Terpenoid Rehmannia glutinosa TH↑, GDNF↑ [100] Paeoniflorin Terpenoid Paeonia lactiflora LC3-II↑, LAMP2a↓, degradation of α-synuclein↑ [101,102] Isoborneol Terpenoid Many medicinal plants reactive oxygen species↓, caspase-3 activity↓, Bax/Bcl-2 ratio↓, JNK activation↓ [103] 10-O-trans-p-Coumaroylcatalpol (OCC) Terpenoid Premna integrifolia Linn a-syn aggregation↓, oxidative stress↓ [104] 2.1. Flavonoid and polyphenol compounds Baicalein (1), which is a flavonoid monomer compound extracted from the Lamiaceae plant Scutellaria baicalensis has extensive pharmacological effects. The study by Mu et al. showed that baicalein could exert protective effects on dopaminergic neurons in C57BL/6 mice with neuronal injury induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and could significantly increase the number of dopaminergic neurons due to its excellent anti-oxidative stress properties [40]. In addition, Li et al. also found that baicalein could also effectively attenuate progressive degeneration of dopaminergic neurons regulated by inflammation [41]. The study by Yu et al. also indicated that baicalein could exert anti-paralysis agitans effects in PD through the regulation of the balance between the neurotransmitters GABA and Glu in the basal ganglia [42]. Importantly, Zhu et al. reported that low micromolar concentrations of baicalein, especially its oxidized forms, inhibit the formation of α-synuclein fibrils. In addition, existing fibrils of α-synuclein are disaggregated by baicalein. Thus, these observations suggest that baicalein and similar compounds may have potential as therapeutic leads in combating Parkinson's disease [43]. Furthermore, Zhang et al. showed that not only could Nrf2 siRNA transfection and the use of an HO-1 inhibitor significantly attenuate the cell protective function of baicalein, but they could also lead to the significant selective inhibition of protein kinase C (PKC), PI3K, and Akt which reduces the cell protective function of baicalein. Therefore, the above results comprehensively indicated that the anti-PD function of baicalein is very likely associated with Nrf2/HO-1 activation and the activation of the PKC and PI3K/Akt signalling pathways [44] (Fig. 3). Quercetin (2) is present in the flowers, leaves, and fruits of many plants. Haleagrahara et al. treated rats with PD induced by 6-OHDA with quercetin and found that this flavonoid exerted anti-PD functions through a significant increase in the levels of antioxidant enzymes in the rats [45]. In addition, Zhang et al. showed that quercetin inhibited the inducible nitric oxide synthase/nitric oxide (iNOS/NO) system and the expression of pro-inflammatory factors in PD animal models, which induced neuroprotective effects [46]. Furthermore, quercetin can bind covalently with α-synucein in 1 to 1 ratio. The formed quercetin-α-synuclein adducts attach to the α-synuclein oligomers or monomers, improving hydrophilic property of the surface and inhibiting further fibrillation. Oxidized by dissolving oxygen, quercetin forms chalcantrione, benzyfuranone, quercetinchinone, and other products. These products react with α-synuclein and elevate the polarity and hydrophilicity, making the inhibition more effective [47]. Puerarin (3) is a flavonoid glycoside component extracted from the Fabaceae plant Pueraria mirifica. Zhu et al. treated PD mice with puerarin and showed that puerarin produced excellent anti-PD effects through the inhibition of the degeneration of dopaminergic neurons, an increase in the number of tyrosine hydroxylase (TH)-positive neurons, and an increase in the expression of glial cell-derived neurotrophic factor (GDNF) [48]. Wang et al. reported that puerarin exerted significant protective effects on PC-12 cells in the setting of MPP+-induced apoptosis through the inhibition of the JNK signalling pathway, which suggests that puerarin can exert certain protective effects in cases of PD-induced neuronal injury (Fig. 3) [49]. The study by Zhu et al. also indicated that puerarin treatment led to significant protective effects on SH-SY5Y cells in the setting of MPP+-induced apoptosis and that the main mechanism occurred through the activation of the PI3K/Akt signalling pathway, which inhibits P53 accumulation in nuclei, and the caspase-3-dependent programmed cell death process [50]. Furthermore, the other 2 active components derived from Pueraria, daidzein (4) and genistein (5), have demonstrated the ability to inhibit caspase-8 activity and to partially inhibit caspase-3 activity; therefore, they exhibit resistance to the cytotoxicity induced by 6-OHDA in PC12 cells [51]. These 2 active components also exert certain neuroprotective effects, and thus, they are predicted to have certain anti-PD effects. Hyperoside (6), also known as quercetin-3-O-β-d-galactopyranoside, is present extensively in Hypericaceae and Rosaceae plants. Liu et al. showed that the application of hyperoside in PD models in which cytotoxicity in PC12 cells was induced by hydrogen peroxide and tert-butyl hydroperoxide (T-BHP) could effectively attenuate cytotoxicity induced by the above 2 substances and could significantly reduce the extracellular lactate dehydrogenase (LDH) level in PC12 cells [52]; these findings indicate that hyperoside exhibits prominent antioxidant activities. The above features suggest that hyperoside is likely to become an excellent lead component of anti-PD therapies. Several studies have demonstrated that increased apoptosis plays an essential role in neurodegenerative disorders. Naringin (7) is a major flavanone glycoside obtained from tomatoes, grapefruits, and many other citrus fruits. which showed significant antiapoptotic effects in rotenone-treated human SH-SY5Y cells by inhibiting phosphorylation of JNK and P38, as well as the activation of caspase-9, PARP, and caspase-3 [53]. Moroever, The study by Wang et al. demonstrated that Naringin could also suppressed LPS-induced PC12 cell apoptosis by mediating the expression of a series of caspase-3-related proteins and some anti-oxidation and anti-inflammatory mechanism [54]. Thus, the above studies showed that Naringin can be utilized as a potential drug for the treatment of neurodegenerative disorders(e.g.PD disorders). In addition to the above natural products, some polyphenol compounds(such as curcumin, epigallocatechin gallate, resveratrol) also exhibit excellent therapeutic effects on PD. Curcumin (8) is the major yellow pigment extracted from turmeric, a commonly used spice in Asian cuisine. Liu et al. found that curcumin could protect against A53T α-synuclein-induced cell death in a dose-dependent manner and reduce mutant α-synuclein-induced intracellular reactive oxygen species (ROS) levels, mitochondrial depolarization, cytochrome c release, and caspase-9 and caspase-3 activation [55]. The study by N. Pandey et al. further showed that curcumin could also inhibit the aggregation of α-synuclein, disrupt preformed aggregates and increase the solubility of AS in cells that contain aggregates [56]. Epigallocatechin gallate(EGCG) (9) is abundantly present in green tea. EGCG could efficiently inhibit the fibrillogenesis of both α-synuclein and amyloid-β by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates [57]. Further study indicated that EGCG also has the ability to convert large, mature α-synuclein and amyloid-β fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells [58]. Resveratrol(10), a natural polyphenol, is abundant in the skin of grapes, blueberries, peanut, raspberries and mulberries. The study by Jin et al. demonstrated that long-term treatment with resveratrol significantly ameliorates 6-OHDA-induced brain injury and resveratrol could also suppressed the 6-OHDA-induced over expressions of COX-2 and TNF-α mRNA and protein in Parkinson model rats. These results indicated that resveratrol exerts a neuroprotective effect [59]. Further research had shown that one of the potential mechanism underlying the neuroprotective effects of resveratrol was that the overexpression of miR-214 in PD midbrain resulted in a decrease of a-synuclein expression and aggregation [60] (Figs. 1 and 2). Fig. 1 Download high-res image (441KB)Download full-size image Fig. 1. The Chemical structures of flavonoid compounds. Fig. 2 Download high-res image (175KB)Download full-size image Fig. 2. The Chemical structures of polyphenol compounds. Fig. 3 Download high-res image (604KB)Download full-size image Fig. 3. The relationship between some flavonoid compounds and PI3K/Akt signaling pathway. 2.2. Phenylpropanoid (coumarin) compounds Danshensu (11), also known as salvianolic acid A, is derived from the Lamiaceae plant Salvia miltiorrhiza Bunge. The report by Wang et al. showed that danshensu exhibits excellent antioxidant and anti-apoptotic activities; therefore, it might effectively regulate Bcl-2 and Bax expression to induce effective inhibitory effects on MPP+-induced cytotoxicity in SH-SY5Y cells. These results also suggested that danshensu could exert active therapeutic effects in neurodegenerative diseases such as PD [61]. In addition, Tian et al. reported that salvianolic acid B (12), another active substance present in Salvia miltiorrhiza, could effectively inhibit 6-OHDA-induced apoptosis in SH-SY5Y cells through a reduction in caspase-3 activity and cytochrome c release [62]. In addition, the study by Zhang et al. indicated that salvianolic acid B could also reduce MPP+-induced apoptosis of SH-SY5Y cells through a reduction in oxidative stress [63]. Eleutheroside B (13) is an important active component of the Araliaceae plant Eleutherococcus senticosus. The study by Yang et al. showed that eleutheroside B demonstrated a protective function on MPP+-induced cell injury in PC12 cells and that the mechanism might be associated with an increase in the phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2) proteins and prevention of the induction of c-fos and c-jun overexpression [64]. Magnolol (14) is an active component of the Magnoliaceae plant Magnolia officinalis. It exhibits very strong anti-microbial and pharmacological effects. In the study by Chen et al., apomorphine was given to PD mice that were injured by 6-OHDA induction, which resulted in a change in the contralateral rotation status; this was followed by treatment with magnolol. The results showed that magnolol could increase the DA level in the striatum through a reduction in TH and could also improve the pathological status of contralateral rotation tremors [65]. Muroyama et al. also showed that magnolol could reduce reactive oxygen species in PD models both in vivo and in vitro because of its excellent antioxidant properties and that it could exhibit anti-PD effects through an increase in the levels of DAT and TH in PD animal models [66]. Chen et al. applied magnolol in a model of local cerebral ischaemia to show that it could exert neuroprotective effects through an effective reduction in iNOs and nitrotyrosine. The underlying mechanism that produced this effect involved the downregulation of the p38/MAPK signalling pathway and the reduction in the level of C/EBP homologous protein (CHOP) [67] (Fig. 5). Fraxetin (15), also known as ash tree lactone, is derived from the bark of the Oleaceae plant Fraxinus bungeana. Molinajiménez et al. studied fraxetin in a rotenone-induced cytotoxicity model in SH-SY5Y cells (a PD model) and showed that it could exert certain anti-PD effects through an increase in the level of reduced glutathione and a reduction in lipid peroxidation reactions [68]. Esculin (16) is an active substance in the Hippocastanoideae plant Aesculus hippocastanumlinn. Zhao et al. applied esculin in a DA-induced PD model in SH-SY5Y cells and showed that esculin could exert significant anti-PD effects through a reduction in the intracellular level of reactive oxygen species, protection of mitochondrial membrane potential, increase of the levels of superoxide dismutase (SOD) and reduced glutathione (GSH), regulation of the expression of P53, Bax, and Bcl-2, inhibition of the release of cytochrome c and apoptosis-inducing factors, and inhibition of caspase-3 activity [69]. Umbelliferone (17), a member of coumarin derivatives, widely exists in a range of fruits, vegetables, and herbs with anti-oxidant and free radical scavenging properties [70]. The study by Sudhakar R et al. showed that the neuroprotective effect of Umbelliferone is linked to their ability to restore GSH levels and prevent apoptosis in a mouse Model of Parkinson's Disease [71]. In addition, umbelliferone has an important feature that it can cross the blood–brain barrier [71]. Thus, the above effectiveness indicates that umbelliferone have the potential to protect in neurodegenerative disorders such as PD (Fig. 4). Fig. 4 Download high-res image (429KB)Download full-size image Fig. 4. The Chemical structures of phenylpropanoid compounds. Fig. 5 Download high-res image (499KB)Download full-size image Fig. 5. The relationship between Magnolol and p38/MAPK signaling pathway. 2.3. Quinone compounds 2-methoxy-6-acetyl-7-methyljuglone (MAM) (18) is an extract with a naphthoquinone structure that is derived from the dried rhizome of the traditional Chinese medicine Fallopia japonica. Li et al. added MAM to culture medium containing PC12 cells in which the oxidizing agent T-BHP was used to induce apoptosis and showed that MAM could block nuclear fragmentation and the accumulation of apoptotic bodies (markers of apoptosis) in a dose-dependent manner. Therefore, this compound was predicted to have a specific anti-PD effect. Further in-depth studies showed that the mechanism of its anti-apoptotic function involved significant inhibition of T-BHP-induced phosphorylation of ERK1/2, JNK, and p38MAPK. Therefore, the anti-PD effect of MAM might be associated with the ERK1/2, JNK, and p38MAPK signalling pathways [72] (Fig. 7). Thymoquinone (19) is a major active substance found in the seeds of Nigella sativa. It is known for its excellent anti-oxidant and anti-inflammatory properties [73,74]. Further studies by Radad et al. showed that thymoquinone could effectively reduce the rate of MPP+-induced death of dopaminergic neurons in rat brain by 40%; similarly, it could also reduce the death rates in short- and long-term rotenone-induced toxicity models in dopaminergic neurons of rat brain by 33% and 24%, respectively. And it could also effectively protect cultured hippocampal neurons against α-synuclein-induced synapse damage and inhibition of synaptic activity [75]. Therefore, thymoquinone was predicted to be a potentially useful leading compound in the development of anti-PD drugs [76]. Alaternin (20) is an alcohol-extracted active substance found in cassia seeds, which are used in traditional Chinese medicine. Early studies showed that alaternin could effectively regulate peroxynitrite-mediated nitration and that it was an antioxidant [77]. Shin et al. applied alaternin in a transient bilateral common carotid artery ischaemia model to effectively reduce the level of thiobarbituric acid products in hippocampal tissues of mice, which indicates its antioxidant and free radical-scavenging abilities. In addition, alaternin could also significantly reduce the levels of microglia and iNOS in a mouse model, which indicates its anti-inflammatory properties [78]. Therefore, alaternin is expected to become a candidate compound in anti-PD drug research (Fig. 6). Fig. 6 Download high-res image (126KB)Download full-size image Fig. 6. The Chemical structures of quinone compounds. Fig. 7 Download high-res image (454KB)Download full-size image Fig. 7. The relationship between 2-methoxy-6-acetyl-7-methyljuglone and ERK 1/2, JNK signaling pathway. 2.4. Saponin compounds Astragaloside (21) (AS-IV) is derived from the dried tuberous root of the classic traditional Chinese medicine Astragalus. Chan et al. showed that AS-IV could increase the nitric oxide synthase (NOS) level in a 6-OHDA-induced dopaminergic neuron injury model, which resulted in protective effects on dopaminergic neurons. In addition, it also promoted neurite outgrowth and increase TH and NOS immunoreactivities in dopaminergic neurons, which led to specific effects that promoted neuronal proliferation [79]. Based on this, Zhang et al. used SH-SY5Y cells as carriers to further study AS-IV in an MPP+-induced neurotoxicity model and showed that it could significantly decrease intracellular reactive oxygen species, the Bax/Bcl-2 ratio, and caspase-3 activities to produce excellent neuroprotective effects [80]. In summary, AS-IV is expected to become a leading compound in the field of anti-PD research. The Araliaceae plant, ginseng, is hailed as the “king of herbs”. It is the best product for “nourishing Yin and tonifying Yang, and for strengthening Qi and securing essence”. It contains many saponin and polysaccharide components such as ginsenoside Rb1, Rb2, Rb3, Rc, Rd, Rg1, and Re, of which Rb1, Rd, Rg1, and Re all exert obvious anti-PD effects. Ginsenoside Rb1 (22) could significantly decrease the amount of lactate dehydrogenase (LDH), which is a marker of neuronal injury, in matrix in a glutamate-induced neurotoxicity model in embryonic mice. Ginsenoside Rb1 could also significantly increase the number and length of neurites of surviving dopaminergic neurons that were damaged by glutamate [81]. Furthermore, Ginsenoside Rb1 was shown to inhibit α-syn fibrillation and toxicity in vitro and to be able to disaggregate preformed fibrils and block the α-syn seeded polymerization possibly by binding and stabilizing non-toxic α-syn oligomers without β-sheet content [82]. Ginsenoside Rd (23) has excellent anti-inflammatory properties. It was able to reduce NO formation and PEG2 synthesis in a lipopolysaccharide (LPS)-induced neurodegeneration model, which led to neuroprotective effects [83]. The application of ginsenoside Re (24) in an MPTP-induced PD mouse model could effectively upregulate the amount of Bcl-2 protein, downregulate Bax and the release of iNOS protein, and inhibit caspase-3 activation, which demonstrates its excellent anti-apoptotic function in neurons [84]. Ginsenoside Rg1 (25) could produce excellent neuroprotective effects due to its significant antioxidant properties in a hydrogen peroxide-induced injury model in PC12 cells. Further in-depth studies have indicated that this mechanism might be associated with the downregulation of the phosphorylation and nuclear transport of NF-κB/p65 in the NF-κB signalling pathway and the inhibition of the activities of the threonine kinase (Akt) and the ERK1/2 pathways [85] (Fig. 9). Notoginsenoside Rg1 (26) is derived from the dried roots and rhizomes of the natural medicine Panax notoginseng. The study by Zhang et al. indicated that the levels of c-Fos, GFAP, GDNF, NF-KB, TNF-α, and IL-lp were increased while the expression of GDNF was decreased in PD mice. When notoginsenoside Rg1 was given to PD mice, the above indicators demonstrated a clear inverse phenomenon. Therefore, it was predicted that notoginsenoside Rg1 might be used in the treatment of PD [86]. Furthermore, relevant studies have shown that panaxatriol saponin (27) derived from Panax notoginseng also exerted certain anti-PD effects. The redox protein thioredoxin-1 (TRX-1) is a multi-functional protein with redox functions that plays an important role in neuronal differentiation and regeneration [87]. The application of panaxatriol saponins in cell or animal models of PD resulted in an effective increase in TRX-1 expression, which led to certain anti-PD effects (Fig. 8). Fig. 8 Download high-res image (360KB)Download full-size image Fig. 8 Download high-res image (462KB)Download full-size image Fig. 8. The Chemical structures of saponin compounds. Fig. 9 Download high-res image (593KB)Download full-size image Fig. 9. The relationship between Ginsenoside Rg1 and NF-κB signaling pathway. 2.5. Alkaloid compounds Ligustrazine (28) is an effective tetramethylpyrazine alkaloid that may be extracted from Ligusticum striatum, which is used in traditional Chinese medicine. It has brain protective properties, improves microcirculation, and inhibits neuronal apoptosis. A further study by Zhu et al. showed that ligustrazine exerted a protective effect on MPTP-induced dopaminergic neuron injury in mice; in addition, the protective mechanism might be associated with the upregulation of the levels of SOD and GSH in the murine substantia nigra [88]. The report by Michel et al. revealed that the anti-PD effect of ligustrazine was achieved mainly through its excellent anti-inflammatory, antioxidant, and anti-apoptotic properties. Furthermore, in-depth molecular mechanistic studies have indicated that the functions of ligustrazine described above were closely associated with a reduction in the Bax/Bcl2 ratio in the mitochondrial apoptosis pathway and the downregulation of the Nrf2/HO-1 signalling pathway [89] (Fig. 11). Nicotine (29), a tobacco alkaloid, is an alkaloid present in the Solanaceae plant. Relevant reports have shown that it exerts significant anti-PD effects. The major mechanism involves a reduction in the intracellular calcium ion concentration in neurons after which many downstream signalling pathways, including the cell apoptosis pathway and the NO-cGMP pathway, are affected. Next, neuronal excitability is increased, and neurotrophic factors are activated, which results in a series of neuroprotective activities [90-92]. In addition, the study by Hong et al. indicated that nicotine could inhibit α-synuclein fibrillation in a concentration-dependent manner and stabilize soluble oligomeric forms. Thus, it potentially might help in developing novel therapeutic solutions for PD [93]. Isorhynchophylline (IsoRhy) (30) is an alkaloid with a 4-ring structure that may be extracted from the Rubiaceae plant Uncaria rhynchophylla. The report by Lu et al. showed that because of its characteristic autophagic effect, IsoRhy could promote the clearance of wild type, A53T, and A30P α-syn monomers, α-syn oligomers, and α-syn/synphilin-1 aggregates in neurons through the ALP. In addition, it could also reduce the levels of wild type and A53T α-syn proteins in dopaminergic neurons [94]. In summary, IsoRhy is predicted to have preventive and therapeutic value in the treatment of neurodegenerative diseases such as PD. l-stepholidine (31) is an active tetrahydroprotoberberine substance found in the traditional Chinese medicine Stephania japonica. The study by Mo et al. showed that l-stepholidine could antagonize the activity of the D2-like receptor in a PD mouse model and could stimulate the 5-HT1A receptor, which prevents movement disorders in a mouse model of PD induced by l-DOPA [95]. Therefore, this compound may be combined with l-DOPA as a PD therapy to reduce severe adverse reactions induced by l-DOPA (Fig. 10). Fig. 10 Download high-res image (179KB)Download full-size image Fig. 10. The Chemical structures of alkaloid compounds. Fig. 11 Download high-res image (778KB)Download full-size image Fig. 11. The relationship between Ligustrazine and mitochondrial apoptosis signaling pathway. 2.6. Terpenoid compounds Triptolide (32) is a diterpene lactone epoxide compound extracted from roots, leaves, flowers, and fruits of the Celastraceae plant Tripterygium wilfordii. It can inhibit microglial activity in an MPP+-induced dopaminergic neuron injury model to control microglia-related inflammatory reactions. In addition, its excellent neuroprotective effects are demonstrated by its ability to inhibit the release of pro-inflammatory factors, TNF-α and IL-1h, in an LPS-induced dopaminergic neuron injury model [96,97]. The study by Hu et al. further showed that the neuroprotective mechanism of triptolide primarily involved the upregulation of the expression of LC3-II protein in the cell autophagy pathway and the increase in the number of autophagosomes produced by the accumulation of GFP-LC3-II, which promoted α-synuclein clearance (Fig. 13) [98]. Ginkgolide B (33) is the strongest lactone out of the active components of ginkgo biloba. Meng et al. reported that, in a model of 6-OHDA-induced neuronal apoptosis, ginkgolide B could effectively inhibit caspase-3 activity, increase the level of Calbindin D28k mRNA (Calbindin D28K is a classical calcium-binding protein closely associated with neurodegeneration and neuronal apoptosis through the regulation of calcium ion balance), and downregulate intracellular calcium concentrations to induce neuroprotective effects [99]. Catalpol (34) is an iridoid active substance from the well-known traditional Chinese medicine Rehmannia glutinosa. The study by Xu et al. showed that in an MPTP-induced neurodegenerative mouse model, catalpol significantly increased the numbers of TH neurons in the substantia nigra pars compacta as well as DAT and GDNF in the striatum, which attenuated MPTP-induced neurotoxicity and neurodegenerative changes [100]. Paeoniflorin (35) is a monoterpene glycoside component in the traditional Chinese medicine Paeonia lactiflora. Cao et al. reported that paeoniflorin could upregulate LC3-II protein in the ALP, inhibit the overexpression of lysosome-associated membrane protein 2a (LAMP2a), and reduce Ca2+ influx through the acid-sensing ion channel (ASI1a) to produce potential protective effects in models of MPP+- or acid-induced neuronal apoptosis [101]. Further studies by Cai et al. showed that Paeoniflorin could significantly upregulate both autophagy and ubiquitin-proteasome pathways, promoting the degradation of α-synuclein, and reducing cell damage [102] (Fig. 13). Isoborneol (36) is a monoterpene alcohol compound present in various medicinal plants. The study by Tian et al. showed that in a 6-OHDA-induced PD model, isoborneol could not only effectively reduce the intracellular levels of reactive oxygen species and Ca2+ influx but could also reduce a series of effects including caspase-3 activity, the Bax/Bcl-2 ratio, and JNK activation, which demonstrates its excellent anti-apoptotic effects [103]. 10-O-trans-p-Coumaroylcatalpol (OCC) (37) is a major ingredient of Premna integrifolia Linn. Virendra et al. applied OCC in Caenorhabditis elegans to show that it has the ability to ameliorate a-syn aggregation, reduce oxidative stress and promote longevity in C. elegans via activation of longevity promoting transcription factor DAF-16 [104]. Thus, OCC may serve as a lead compound of plant origin for neurodegenerative disorders (e.g.PD disorders) (Fig. 12). Fig. 12 Download high-res image (300KB)Download full-size image Fig. 12. The Chemical structures of terpenoid compounds. Fig. 13 Download high-res image (363KB)Download full-size image Fig. 13. The relationship between some terpenoid compounds and cell autophagy pathway signaling pathway. 3. Conclusion PD is one of the most common neurodegenerative diseases worldwide, and effective treatments for it are yet to be found. Because the causes of PD are unknown, current treatments focus on managing patients' symptoms and on increasing DA levels in the respective brain areas of nerve cells to protect them. However, DA-based treatment strategies are often associated with detrimental side effects or unsatisfactory treatment outcomes. Thus, effective new treatment strategies for PD are urgently needed given the increasing number of PD patients worldwide. With further study of the pathogenesis of PD as well as deeper revealing of the pharmacological effects of various natural products, more and more monomer components derived from natural products are found to have anti-PD efficacy in vivo or vitro. However, many of these monomer components outlined above could not be directly used as drugs for the treatment of PD and related disorders. Therefore, we speculate that detailed investigations into the structure–activity relationships of natural products outlined above may guide the design of novel therapeutic drugs in Parkinson's disease which possess enhanced properties in vivo (e.g. ability to penetrate the blood–brain barrier), but which retain the bioactivity characteristic of the natural product scaffold. Thus, these monomer components outlined above could represent starting points to the development of innovative anti-PD drugs. Acknowledgements Financial support from State Administration of Traditional Chinese Medicine (No. JDZX2015210); Health and Family planning commission of Sichuan province (No. 150194); National Natural Science Foundation of China (NSFC 81602950) and Administration of Traditional Chinese Medicine of Sichuan (No. 2016Q001) is gratefully acknowledged. References [1] W. Dauer, S. Przedborski Parkinson's disease: mechanisms and models Neuron, 39 (2003), p. 889 ArticleDownload PDFView Record in Scopus [2] S. Phani, J.D. Loike, S. Przedborski Neurodegeneration and inflammation in Parkinson's disease Park. Relat. Disord., 18 (Suppl 1) (2012), p. S207 ArticleDownload PDFView Record in Scopus [3] T. Pringsheim, N. Jette, A. Frolkis, T.D. Steeves The prevalence of Parkinson's disease: a systematic review and meta-analysis Mov. Disord. Official J. Mov. Disord. Soc., 29 (2014), p. 1583 CrossRefView Record in Scopus [4] C.W. Olanow, D.R. Wakeman, J.H. 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