Neuroprotective mechanisms of plant extracts against MPTP induced neurotoxicity: Future applications in Parkinson’s disease

G Model BIOPHA 4584 No. of Pages 11

Biomedicine & Pharmacotherapy xxx (2016) xxx–xxx

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Neuroprotective mechanisms of plant extracts against MPTP induced neurotoxicity: Future applications in Parkinson’s disease Abdelrahman Ibrahim Abushouka,b,c , Ahmed Negidac,d,e , Hussien Ahmedc,d,e , Mohamed M. Abdel-Daimf,* a

Faculty of Medicine, Ain Shams University, Cairo, Egypt NovaMed Medical research Association, Cairo, Egypt Medical Research Group of Egypt, Cairo, Egypt d Faculty of Medicine, Zagazig University, Zagazig, El-Sharkia, Egypt e Student Research Unit, Zagazig University, Zagazig, El-Sharkia, Egypt f Pharmacology department, Faculty of veterinary medicine, Suez Canal University, Ismailia, 41522, Egypt b c

A R T I C L E I N F O

Article history: Received 27 September 2016 Received in revised form 3 November 2016 Accepted 16 November 2016 Keywords: Parkinson’s disease Mptp Plant extracts Neuroprotection

A B S T R A C T

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, affecting about seven to 10 million patients worldwide. The major pathological features of PD are loss of dopaminergic neurons in the nigrostriatal pathway and accumulation of alpha-synuclein molecules, forming Lewy bodies. Until now, there is no effective cure for PD, and investigators are searching for neuroprotective strategies to stop or slow the disease progression. The MPTP (1-methyl-4phenyl-1,2,3,6-tetrahydropyridine) induced neurotoxicity of the nigrostriatal pathway has been used to initiate PD in animal models. Multiple experimental studies showed the ability of several plant extracts to protect against MPTP induced neurotoxicity through activation of catalase, superoxide dismutase, and glutathione reductase enzymes, which reduce the cellular concentration of free radicals, preventing intracellular Ca++ release and subsequent apoptosis signaling. Other neuroprotective mechanisms of plant extracts include promoting autophagy of alpha-synuclein molecules and exerting an antiapoptotic activity via inhibition of proteolytic poly (ADP-ribose) polymerase and preventing caspase cleavage. The variety of neuroprotective mechanisms of natural plant extracts may allow researchers to target PD progression in different pathological stages and may be through multiple pathways. Further investigations are required to translate these neuroprotective mechanisms into safe and effective treatments for PD. ã 2016 Elsevier Masson SAS. All rights reserved.

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary of neuroprotective effects of different plant Antioxidant activity . . . . . . . . . . . . . . . . . . . . . 2.1. Antiapoptotic effects . . . . . . . . . . . . . . . . . . . . . 2.2. Autophagy enhancement . . . . . . . . . . . . . . . . . 2.3.

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Abbreviations: ASK-1, Apoptosis signal regulating kinase-1; BDNF, Brain Derived Neurotrophic Factor; CI, Chrysanthemum indicum Linn; DAT, Dopamine transporter; EGb761, Ginkgo biloba extract 761; EGCG, Epigallocatechin-3-gallate; GR, Glutathione Reductase; H2O2, Hydrogen peroxide; HO-1, Heme-Oxygenase 1; JNK, c-Jun NH2terminal kinase; LAMP-2A, Lysosome associated membrane protein type 2A; LC3-II, Light chain 3- phosphatidylethanolamine conjugate; MAPK, mitogen activated protein kinases; MDA, Malondialdehyde; MPTP, 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine; NADP(H)QO-1, Nicotine-Adenine Diphosphonucleotide, Quinone oxidoreductase 1 (NQO1); NBP, Dl-3-n-butylphthalide; NF-Kb, Nuclear factor- Kappa-B; NO, Nitric oxide; Nrf-2, Nuclear factor-2 Erythroid-2; PARP, Poly (ADP-ribose) polymerase; PC12, Pheochromocytoma cells 12; PCA, Protocatechuic acid; PF, Paeoniflorin; PGC, Peroxisome proliferator-activated receptor gamma coactivator 1; PI3K/Akt, Phosphatidylinositol 3-kinase/Protein Kinase B; ROS, Reactive oxygen species; SAC, S-Allylcysteine; SH-SY5Y, Human Neuroblastoma cells; SOD, Superoxide Dismutase; UPS, Ubiquitin Protease system. * Corresponding author. E-mail addresses: [email protected], [email protected] (M.M. Abdel-Daim). http://dx.doi.org/10.1016/j.biopha.2016.11.074 0753-3322/ã 2016 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: A.I. Abushouk, et al., Neuroprotective mechanisms of plant extracts against MPTP induced neurotoxicity: Future applications in Parkinson’s disease, Biomed Pharmacother (2016), http://dx.doi.org/10.1016/j.biopha.2016.11.074

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2.4. Specific neuroprotective mechanisms Summary of preclinical trials . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflicts of interest . . . . . . . . . . . . . . . . . . . . Funding source . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction Parkinson’s disease (PD) is the second most common neurodegenerative condition after Alzheimer's disease, affecting about 1% of the worldwide population above 60 years [1]. The major pathological features of PD are loss of dopaminergic neurons in the nigrostriatal pathway and formation of Lewy bodies [2]. Due to death of dopaminergic neurons, PD patients suffer from motor symptoms such as tremors, rigidity, and bradykinesia which cause disabilities and affect their quality of life [3]. To the moment, there is no effective cure for PD, and current medications aim at controlling the symptoms and improving the quality of life for PD patients [4]. The main pathological pathway, responsible for death of dopaminergic neurons in PD, is not yet known [3]. Population based studies identified mutations in some genetic loci that can predispose to the development of sporadic PD [5,6]. The first identified genetic mutation was found in the alpha-synuclein gene [7]. Alpha-synuclein is an elongated, unstructured presynaptic phosphoprotein that is believed to contribute to the function of synaptic vesicles and is normally cleaved by unidentified synucleinases [8]. Genetic mutations, oxidative stress, dopamine depletion, and proteosomal dysfunction can induce hyperphosphorylation, misfolding and aggregation of alpha-synuclein molecules [9], forming eosinophilic inclusions, known as Lewy bodies [10]. The aggregation of these molecules in a toxic, misfolded form may contribute to neuronal cell death [11]. Another common mutation occurs in the parkin ligase expression gene [12], which codes for a ligase enzyme that adds ubiquitin molecules to mark the target proteins for proteosomal clearance [13]. Loss of its enzymatic function causes accumulation of its substrates such as fructose-1,6-bisphosphatase 1 (FBP1) and aminoacyl-tRNA synthetase-interacting multifunctional protein type 2 (AIMP2), leading to neuronal cytotoxicity [14]. Epidemiological studies showed a link between exposure to environmental factors such as organophosphorus compounds, viral encephalitis, or repeated head trauma and the risk of developing PD [15,16]. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is a neurotoxin that has the ability to cross the blood brain barrier and damage dopaminergic neurons in the nigrostriatal pathway [17]. Although MPTP itself is not toxic, it is transformed by monoamine peroxidase enzyme to MPP+ which binds to dopamine transporters (DAT), causing inhibition of dopamine uptake and depletion of its cerebral levels [18]. When transported inside the neuronal bodies, MPP+ passes to the mitochondria and impairs oxidative phosphorylation through inhibition of complex I (NADPH-ubiquinone oxidoreductase I) in the electron transport chain [17,19,20]. This inhibition leads to elevated Ca++ levels, formation of free radicals, and impairment of ATP production causing inability of the mitochondria to supply the cell with energy [21]. The MPTP induced neurotoxicity of the nigrostriatal pathway is used to initiate PD in animal models [22,23]. Experiments on MPTP treated animal models led to better understanding of PD pathology including microglial activation and oxidative stress, and allowed investigators to test neuronal replacement therapies for this neurodegenerative condition.

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Due to the progressive nature of PD, investigators are searching for neuroprotective agents that can stop the underlying pathological condition and therefore, prevent further neuronal death. The literature suggests that several medicinal plants and their active constituents and extracts exert neuroprotective effects against neuronal cell death [24]. These plants have been traditionally used in folk medicine for centuries [25], and currently, they are widely used in traditional Chinese medicine for treating neurological disorders such as general paralysis, epilepsy, cerebrovascular disorders, and neurodegenerative diseases [26–28]. Recently, scientific research on medicinal plants is getting more attention because the identification of their active ingredients can improve drug manufacturing [29] and studying their mode of action may help identifying new therapeutic targets. In this article, we reviewed preclinical trials that investigated the neuroprotective effects of plant extracts against MPTP induced neurotoxicity. 2. Summary of neuroprotective effects of different plant extracts Preclinical trials identified several mechanisms, underlying the observed neuroprotective effects of medicinal plants, including antioxidant, anti-inflammatory, antiapoptotic, and neurotrophic mechanisms [30]. Understanding these mechanisms at the molecular level will help developing novel neuroprotective agents for PD. 2.1. Antioxidant activity This is the most commonly reported mechanism of action for plant extracts in attenuating MPTP induced cytotoxicity and improving cell viability (Table 1). The formation of reactive oxygen species (ROS) results in mitochondrial transmembrane potential collapse and dysfunction of the mitochondrial respiratory chain complex-1, which ultimately leads to increased cytosolic concentrations of Ca++ and mitochondrial cytochrome C, initiating apoptosis signaling pathways [24]. Therefore, the reduction of cellular free radicals prevents apoptosis and preserves mitochondrial function [30]. Several plants including those of Alpinia oxyphylla, Chrysanthemum indicum Linne (CI), and Chrysanthemum morifolium Ramat (CM) plants can reduce the production of ROS through direct activation or increasing mRNA expression of reductive enzymes such as catalase, superoxide dismutase (SOD), glutathione reductase (GR), and phase two enzyme [Nicotine-Adenine Diphosphonucleotide (NADP(H))-Quinone oxidoreductase 1 (NQO1)] [31–33]. Moreover, numerous compounds such as Ginko biloba extract 761 (EGb761) and S-Allylcysteine (SAC) can attain a free radical scavenging action to inactivate nitrous oxide (NO) and hydrogen peroxide (H2O2) radicals [34,35]. The efficacy of these compounds can be evaluated through measuring the cytoplasmic levels of malondialdehyde (MDA), which acts as an index for lipid peroxidation [36]. In a recent study by Jiang and colleagues (2014), application of gastrodion on MPTP treated SH-SY5Y cells resulted in enhanced nuclear factor-2 Erythroid-2 (Nrf2) nuclear translocation which is upstream of Heme-Oxygenase-1 (HO-1)

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Table 1 shows a list of plant extracts that showed an antioxidant neuroprotective effect against MPTP neurotoxicity in preclinical studies. Plant

Extract or active constituent

Reference

Alpinia oxyphylla Apium graveolens Linn Buddleja officinalis Maxim Cistanche salsa Cruciferous vegetables Dimocarpus longan Lour. flower Allium Stavium Ginkgo biloba leaves Camellia sinensis Ligusticum wallich Franch Lycium barbarum

An ethyl acetate; protocatechuic acid Dl-3-n-butylphthalide Verbascoside Tubuloside B 3H-1,2-dithiole-3-thione protects Dimocarpus longan Lour. flower water extract S-Allylcysteine (Aged Garlic extract) Ginkgo biloba extract EGb 761 Epigallocatechin-3-gallate Tetramethylpyrazine nitrone Lycium barbarum extract

An and Guan et al. [39]. Huang et al. [40]. Sheng et al. [41]. Sheng et al. [30]. Jia et al. [31]. Lin et al. [42]. Rojas et al. [35]. Rojas et al. [34]. Ye et al. [43]. Guo et al. [44]. Yao et al. [45].

antioxidant enzyme gene [37]. Activation of HO-1 results in increased levels of antioxidant substrates such as biliverdin, bilirubin, and ferritin [38]. 2.2. Antiapoptotic effects Caspases are primary mediators of apoptosis through DNA fragmentation and cleavage of various key cellular proteins. Caspase-3, the major member of this cascade, can be activated by oxidative stress, release of mitochondrial cytochrome C (mitochondrial dependent pathway), and caspase-9 activation [46]. Several preclinical studies reported the ability of various plant extracts such as gastrodion, protocatechuic acid (PCA), and ginsenoside RG-1 to inhibit the caspase apoptotic cascade through direct interaction with caspase proteins or inhibition of mitochondrial cytochrome C release (Table 2) [25,47,48]. In an animal study by Bo and colleagues (2005), puerarin (an extract of Pueraria lobata plant) could inhibit caspase-3 like proteins, which mediate delayed neuronal cell death [49]. Other studies attributed the anti-apoptotic effects of gastrodion and gynostemma pentaphyllum polysaccharides to direct inhibition of poly (ADP-ribose) polymerase (PARP) [25,50]. PARP is a nuclear apoptotic enzyme which is activated by caspase-3 cleavage in response to DNA damage and it adds ADP-ribose molecules to DNA point breaks, initiating apoptosis [51]. Elevated free cytosolic Ca++ concentrations can induce apoptotic signaling pathways and activate caspase-3 like proteasomes. In a study by Cao and colleagues (2010), pretreatment of differentiated pheochromocytoma cells (PC12) with paeoniflorin (PF) could prevent Ca++ influx from the extracellular environment, stopping the dependent apoptotic pathway [30]. Another study tested the ability of ginsenoside RG-1 to prevent MPTP toxicity in human neuroblastoma (SH-SY5Y) cells [47]. The study showed that ginsenoside RG-1 may exert its antiapoptotic effect through‘ inhibition of c-Jun NH2-terminal kinase (JNK), a primary member of mitogen activated protein kinases (MAPKs),

which are activated by cellular stress and lead to induction of Fas ligand (FasL) expression and apoptosis [56]. Likewise, induction of Thioredoxin-1 expression in MPTP treated PC-12 cells using Panax notoginseng extract led to inhibition of apoptosis signal regulating kinase-1 (ASK-1), which is a member of the MAPK proapoptotic enzyme family [57,58]. Recent evidence suggests that the neuroprotective effects of some plants such as Yi Gan San and Bacopa monniera extract can be attributed to promotion of Phosphatidylinositol 3-kinase/Protein Kinase B (PI3K/Akt) pathway [59,60], which is a cellular signaling pathway, activated by growth and survival factors and it inhibits the activation of the pro-apoptotic Bcl-2 family members and caspase-3 [61]. The Bcl-2 family proteins include both survival factors such as (BCL-XL) and pro-apoptotic factors such as Bax protein which are usually balanced to allow a normal cell cycle [62]. Recently, it was found that MPTP induced cytotoxicity is mediated by an increased Bax/Bcl-2 ratio, while the neuroprotective effects of gastrodion and phellodendri cortex (PC) extract (Table 3) were attributed to reduction of this ratio [25,55]. 2.3. Autophagy enhancement Inhibition of alpha-synuclein degradation is a major neurotoxic mechanism of MPTP [22]. Recently, plant extracts such as paeoniflorin (PF) and modified yeoldahanso-tang (MYH) were found able to enhance autophagic clearance of toxic cytoplasmic filaments. These results were confirmed by detection of elevated levels of light chain 3- phosphatidylethanolamine conjugate (LC3-II), a protein marker of active autophagy [27,64]. Moreover, the application of MPTP toxins on PC12 cells resulted in overexpression of lysosome associated membrane protein type 2A (LAMP2A), which is directly correlated with the activity of the chaperone mediated autophagy pathway [49]. However, treatment of these cells with PF inhibited the overexpression of LAMP2A [27]. Recent studies over 3-n-butylphthalide (NBP), an oriental plant extract, showed that it increased the accumulation of

Table 2 shows a list of plant extracts that showed the ability to inhibit caspase and poly (ADP Ribose) polymerase enzymes in preclinical studies. Plant

Extract or active constituent

Reference

Alpinia oxyphylla Buddleia lindleyana Buddleja officinalis Maxim Chrysanthemum morifolium Ramat (CM) Cistanche salsa

An ethyl acetate; protocatechuic acid (PCA) Phenylethanoid glycosides Verbascoside CM crude extract Acteoside Polyethanoid glycosides Gastrodin Ginsenoside Rg1 Gynostemma pentaphyllum polysaccharides PC Methanol extract Puerarin Rosmarinic acid

Guan et al. [48]. Li et al. [52]. Sheng et al. [41]. Kim et al. [33]. Pu et al. [53]. Tian et al. [54]. An and Kim et al. [25]. Fang et al. [47]. Deng et al. [50]. Jung et al. [55]. Bo et al. [49]. Du et al. [24].

Gastrodia elata Blume Panax Ginseng Gynostemma pentaphyllum Phellodendri Cortex (PC) Pueraria lobata (Willd.) Rosmarinus officinalis

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Table 3 shows a list of plant extracts that showed the ability to reduce Bax/Bcl-2 ratio and prevent subsequent neuronal apoptosis in preclinical trials. Plant

Extract or active constituent

Reference

Chrysanthemum indicum Linn (CI) Chrysanthemum morifolium Ramat (CM) Dimocarpus longan Lour. flower Gastrodia elata (GE) Blume

CI extract CM extract Apigenin (AP), Galangin and Genkwanin Gastrodin

Gynostemma pentaphyllum Phellodendri Cortex

Gynostemma pentaphyllum polysaccharides PC Methanol extract

Kim et al. [32]. Kim et al. [33]. Liu et al. [63]. An and Kim et al. [25]. Kim et al. [28]. Deng et al. [50]. Jung et al. [55].

autophagosomes and caused upregulation of LC3-II protein [40]. This extract is currently used in stroke clinical trials and represents a promising therapeutic agent for neurodegenerative diseases [65]. 2.4. Specific neuroprotective mechanisms Several preclinical trials reported that using plant extracts such as delta 3,2-hydroxybakuchiol, beta-carbolines, and Ginko biloba extract 761 (EGb761) restored the level of monoamine neurotransmitters in MPTP intoxicated cells to control levels through reversible inhibition of monoamine oxidase enzymes (A and B), and inhibiting the reuptake of dopamine to neuronal cells and therefore, increasing its extracellular concentration [66–68]. On the other hand, in-vitro studies reported the ability of Common flowering quince (FQ) and green tea polyphenols to inhibit MPTP uptake by DAT proteins [29,69]. In a study by Li and colleagues (2003), tripchloride, an extract of the Chinese herb [Tripterygium wilfordii], showed neurotrophic effects by enhancing mRNA expression of brain derived neurotrophic factor (BDNF), a nerve growth factor that can promote axonal elongation and enhance survival of dopaminergic neurons [26]. In another study by Ye and colleagues (2012), epigallocatechin-3-gallate (EGCG), a green tea polyphenol, caused upregulation of peroxisome proliferator-activated receptor gamma

coactivator 1 (PGC-1), resulting in improved mitochondrial function and dopaminergic neuronal survival [43]. The role of hormonal imbalance in PD pathogenesis is an active area of research. Observational studies have shown that PD is generally more common in males than females and that the risk of developing the disease increases significantly in menopausal women, suggesting that lowering estrogen levels are associated with an elevated risk of neurodegenerative diseases [70,71]. An animal trial has shown that estrogen treatment improves motor abilities in mice with MPTP induced parkinsonism [72]. Another study on rodents showed that estrogen protected dopaminergic neurons against MPTP neurotoxicity [73]. Plants such as Sesamum indicum include phytoestrogens which offer neuroprotective advantages with less hormonal effects; therefore, they can be used in males and females to slow the progress of PD [74]. Microglial activation and astrocytic hypertrophy are markers of neuroinflammation [75]. Recent evidence suggests a parallel relationship between local CNS immunity and peripheral systemic immunity through the release of proinflammatory cytokines including IL-1 and IL-6, as well as caspase activation. Accumulation of alpha-synuclein molecules triggers a local immune response, producing a parallel peripheral inflammatory response [76,77]. Amelioration of both immune reactions may alleviate neuroinflammation, and subsequently preserve dopaminergic neurons.

Fig. 1. shows a summary of the neuroprotective mechanisms of natural plant extracts against MPTP toxicity.

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Table 4 summarizes the findings of preclinical trials, arranged by the neuroprotective mechanism of investigated plant extracts. Plant

Extract or active constituents

Extract type

Target cells

Findings

Possible mechanisms

Reference

1. Antioxidant mechanisms Acanthopanacis AS Extract senticosus (AS)

Ethanol based

PC12 cells

The levels of ROS were reduced, as well as LDH leakage.

An and Liu et al. [36].

Alpinia oxyphylla Protocatechuic acid (PCA)

Ethanol based

PC12 cells

AS extract prevented the MPTP induced apoptosis in PC12 cells and increased the cell survival rate. PCA is a useful therapeutic strategy for the treatment of oxidative stress-induced neurodegenerative disease. PCA protected against MPTP toxicity and can have a therapeutic potential in treatment of neurodegenerative diseases. NBP reduced the cytotoxicity of MPTP in PC12 cells.

PCA enhanced the activities of superoxide dismutase and catalase enzymes.

An and Guan et al. [39].

PC12 cells

Guan et al. PCA prevented formation of ROS, GSH depletion, activation of caspase- [48]. 3, and down-regulation of Bcl-2.

Apium graveolens Linn Bacopa monniera (BM)

dl-3-nbutylphthalide (NBP) Bacopa monniera (BM) extract

Water based

SH-SY5Y cells

Bacopa monniera extract protected against MPTP- and paraquat-induced cytotoxicity.

Chrysanthemum indicum Linn (CI)

CI extract

Methanol based

SH-SY5Y cells and lipopolysaccharide stimulated BV-2 microglial cells.

CI extract ameliorated the neuroinflammatory response, induced by various neurotoxins.

Cruciferous vegetables

3H-1,2-dithiole-3thione

SHSY5Y cells

D3T increased the antioxidative defenses of treated cells.

Dimocarpus longan Lour. flower

Dimocarpus longan Lour. flower water extract (LFWE)

Water based

LFWE treated rat models.

Apigenin (AP)

Dimethyl sulfoxide based

PC12 cells

Allium Stavium

S-allylcysteine (SAC) (Aged Garlic extract)

Gastrodia elata (GE) Blume

Gastrodin

Ethanol based or water base Ethanol based

C57BL/6J mice/ Corpus striatum cells. SHSY5Y cells

Dimethyl sulfoxide based

SHSY5Y cells

Ethanol based

MN9D dopaminergic cells

LFWE attenuated MPTP neurotoxicity in nigrostriatal neurons in a dose dependent manner. AP showed neuroprotective effects AP decreased ROS production, against MPTP induced suppressed the increased rate of neurotoxicity in PC12 cells. apoptosis and reduced the Bax/Bcl2 ratio. SAC could protect neurons from SAC reduced superoxide radical MPTP induced oxidative stress. production with up-regulation of CuZn-superoxide dismutase activity. Gastrodion had protective effects Gastrodin inhibited the production of against MPTP-induced ROS and reduced the Bax/Bcl-2 ratio, cytotoxicity in dopaminergic cells. cleaved caspase-3 and PARP proteolysis. Gastrodin upregulated heme Gastrodin showed a partial cytoprotective role in oxygenase-1 (HO-1) expression dopaminergic cell culture. through p38 MAPK/Nrf2 pathway in human dopaminergic cells Vanillyl alcohol reduced the Vanillyl alcohol could protect dopaminergic MN9D cells against elevation of ROS levels, decreased the MPTP-induced apoptosis Bax/Bcl-2 ratio and PARP proteolysis. EGb761 partially prevented the Antioxidant and free radical dopamine-depleting effect of scavenging action. MPTP at 24 h. EGCG suppressed MPTP-induced Antioxidation, scavenging of free injury of PC12 cells. radicals, increasing expression of PGC-1 alpha and anti-apoptosis. Reducing ROS and increasing cellular TBN rescued dopaminergic neurons from MPTP induced anti-oxidative defense capability cytotoxicity. (SOD and GR). Lycium barbarum extract Antioxidative property and protected against MPTP induced restoration of total GSH level. neurotoxicity in C. elegans and PC12 cells. Panaxatriol saponins attenuated Panaxatriol saponins controlled the MPTP induced cell death. redox balance by inducing Thioredoxin-1. Moreover, it inhibited apoptosis signaling.

Vanillyl Alcohol

Ginkgo biloba leaves

PC12cells

Ginkgo biloba extract EGb 761

C-57 black mice/ Corpus striatum cells. PC12 cells

Camellia sinensis Epigallocatechin-3gallate (ECEG) Ligusticum wallich Franch

Tetramethylpyrazine nitrone (TBN)

Ethanol based

SHSY5Y cells

Lycium barbarum

Lycium barbarum extract

Hot water based

PC12 cells and Caenorhabditis elegans.

Panax notoginseng

Panaxatriol saponins

Methanol based

PC12 cells

NBP suppressed the mitochondrial permeability transition and increased the cellular GSH content. BM extract preserved the cellular redox homeostasis and mitochondrial activities by promoting the cell survival (Akt) pathway. CI extract decreased ROS production, reduced the Bax/Bcl-2 ratio, and suppressed the production of prostaglandin E-2 and the expression of cyclooxygenase type-2 (COX-2). It also blocked IkappaB-alpha degradation and activation of NFkappaB in BV-2 cells in a dosedependent manner. It increased the levels of reduced GSH and increased mRNA expression of the gamma-glutamylcysteine ligase catalytic subunit (GCLC), GR, and NQO1 in these cells. Antioxidative, anti-inflammatory, and anti-apoptotic activities.

Huang et al. [40]. Singh et al. [60].

Kim et al. [32].

Jia et al. [31].

Lin et al. [42].

Liu et al. [63].

Rojas et al. [35]. An and Kim et al. [25].

Jiang et al. [37].

Kim et al. [28]. Rojas et al. [34]. Ye et al. [43].

Guo et al. [44]. Yao et al. [45].

Luo et al. [57].

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Table 4 (Continued) Plant

Extract or active constituents

Extract type

Vitis Vinifera (grape) seeds

Resveratrol

C57BL/6 mice/ Resveratrol loaded Corpus striatum nanoparticles cells.

Ripened tomatoes

Lycopene

Water based

C. tinctorius

Hydroxyl Safflor Yellow A (HYSA)

Water based

Valleriana Wallicii Rhizome Piper Longum L.

Valleriana Wallicii Rhizome extract (VWE) Piper Longum alkaloids (PLA)

Methanol based

2. Antiapoptotic effects Gynostemma Gynostemma pentaphyllum pentaphyllum polysaccharides

Ethanol based

Target cells

Resveratrol loaded nanoparticles exerted a significant neuroprotective effect against MPTP neurotoxicity. Resveratrol protected C57BL/6 mice/ Corpus striatum dopaminergic neurons in the SN cells. against MPTP toxicity through regulating inflammatory reactions. Male C57bL/6 mice/ Lycopene protected against MPTP Corpus striatum induced dopaminergic depletion cells. in a dose dependent manner. Adult male Wistar HYSA ameliorated MPTP rats/whole brain neurotoxicity and ischemia/ samples. reperfusion injury. Male C57BL/6 VWE mitigated oxidative stress mice/Corpus and inflammatory damage in PD. striatum cells. Adult male C57BL/6 PLA had neuroprotective and mice/Corpus ameliorative properties in striatum samples. dopaminergic neurons.

Water based

PC12 cells

Chrysanthemum morifolium Ramat (CM)

CM extract

Water based

SH-SY5Y cells

Cistanche salsa

Acteoside

Ethanol based

Cerebellar granule neurons (CGNs)

Polyethanoid glycosides

CGNs

Tubuloside B

PC12 cells

Mice brain mesencephalic cultures PC12 cells

Buddleia lindleyana

Phenylethanoid glycosides

Ethanol based

Buddleja officinalis Maxim

Verbascoside

Ethanol based

Radix Paeoniae alba

Paeoniflorin (PF)

Water based

Rosmarinus officinalis

Rosmarinic acid

Yi-Gan San

Yi-Gan San extract

Water based

SHSY5Y cells

Pueraria lobata (Willd.)

Puerarin

Ethanol based

PC12 cells

Panax Ginseng

Ginsenoside Rg1

PC12 cells

MES23.5 Dopaminergic cells

SHSY5Y cells Water based

Findings

C57BL/6J mice/ Corpus striatum samples.

Possible mechanisms

Antioxidant effect and restoration of Lindner et al. [79] tyrosine hydroxylase expression in the striatum. Resveratrol exerted an antioxidant Lofrumento effect and restored the expression of et al. [80] the suppressor of cytokine signaling1. Lycopene reversed MPTP induced neurochemical deficits, oxidative stress, and apoptosis. Free radical scavenging activity and reduction of inflammatory cytokines (e.g. TNF-a) levels. VWE exerted an antioxidant activity, increased DA levels and expression of growth factors. PLA treatment increased GSH and SOD levels and reduced lipid peroxidation of malondiadehycle.

Inhibiting elevated Bax/Bcl-2 ratio, as well as the release of cytosolic cytochrome c and attenuating caspase-3/9 activation and cleavage of PARP. CM extract attenuated the elevation CM extract showed a potent neuroprotective activity against of reactive oxygen species (ROS) MPTP toxicity. level, increased the Bax/Bcl-2 ratio and inhibited cleavage of caspase-3 and PARP proteolysis. Inhibiting the active caspase-3 Acteoside prevented the MPP +-induced apoptosis and inhibits fragment (17 kDa) and the proteolytic the apoptosis-related pathway. poly (ADP-ribose) polymerase (PARP) fragment (85 kDa) expression. Polyethanoid glycosides inhibited Polyethanoid glycosides exerted apoptosis induced by MPTP in their anti-apoptosis effect by dopaminergic neurons. inhibiting caspase-3 and caspase-8 activities. Tubuloside B attenuated DNA Tubuloside B prevented MPTPinduced apoptosis and oxidative fragmentation and reduced stress intracellular accumulation of ROS. Phenylethanoid glycosides Inhibiting the expression of the protected mesencephalic neurons caspase-3 gene and inducing from MPTP-induced cell death cleavage of PARP. Verbascoside attenuated MPTPVerbascoside attenuated MPTP induced apoptosis and induced apoptotic death, prevented mitochondrial dysfunction. activation of caspase-3 and collapse of mitochondrial membrane potential. PF modulated autophagy in PF reduced cytosolic free Ca++ and models of neuronal injury. caused upregulation of LC3-II protein and overexpression of LAMP2A. Rosmarinic acid restored the Rosmarinic acid had a neuroprotective effect by complex I activity of the ameliorating mitochondrial mitochondrial respiratory chain and dysfunction. inhibited caspase-3 activation. Decreasing caspase-3 activity and Yi-Gan San extract rescued dopaminergic neurons from MPTP increasing activation of the PI3 K/Akt toxicity. pathway. Pretreatment of PC12 cells with Puerarin inhibited the release of puerarin could block MPP mitochondrial cytochrome C to +-mediated apoptosis by cytosol and the loss of mitochondrial inhibiting mitochondrialmembrane potentials. It also reduced dependent caspase cascade. MPTP-induced caspase-3-like activation. Rg1 protected against MPTPInhibition of the activity of JNK and induced apoptosis in SHSY5Y cells. reduction of caspase-3 activity. Rg1 protected against MPTP Rg1 inhibited MPTP induced toxicity by regulating central and apoptosis and microglial activation. It peripheral inflammation. also reduced blood count of T cells and serum concentrations of proinflammatory cytokines. GP showed protective effects against MPTP-induced neuronal apoptosis in PC12 cells.

Reference

Prema et al. [81] Ramagiri et al. [82] Sridharan et al. [83] Bi et al. [84]

Deng et al. [50].

Kim et al. [33].

Pu et al. [53].

Tian et al. [54].

Sheng et al. [30]. Li et al. [52].

Sheng et al. [41].

Cao et al. [27]. Du et al. [24].

Doo et al. [59]. Bo et al. [49].

Fang et al. [47]. Zhou et al. [85]

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Table 4 (Continued) Plant

Extract or active constituents

Extract type

Target cells

Findings

Possible mechanisms

Reference

Coptis Chinensis rhizome

Berberine and coptisine

Water based

SH-SY5Y cells

Treatment with Coptis Chinensis extract improved cell viability and prevented MPTP induced apoptosis.

Friedemann et al. [86]

Ginko biloba L.

Ginkgetin

Water based

C57BL/6J mice/ Corpus striatum samples.

Ginkgetin treatment provided a strong protection from MPTP induced cell damage.

Coptis Chinensis extract increased intracellular ATP concentrations and increased the number of tyrosine hydroxylase positive (dopaminergic) cells. Ginkgetin inhibited the downexpression of tyrosine hydroxylase and SOD. It inhibited cell apoptosis by inhibiting caspase-3 and Bax-Bcl-2 pathways. It also chelated intracellular ferrous iron and upregulated transferrin receptor-1.

PC12 cells

NBP protected PC12 cells against MPTP-induced neurotoxicity.

3. Autophagy enhancement dl-3-nApium butylphthalide (NBP) graveolens Linn Cannabis sativa Delta-9-tetrahydrocannabinolic acid (THCA) and cannabidiol. Eucommia Duzhong ulmoides Olive

Ethanol based

Mice brain mesencephalic cultures

Ethanol based

SHSY5Y cells

Pueraria lobata (Willd.)

Ethanol based

PC12 cells

Modified Yeoldahanso-tang (MYH)

4. Specific neuroprotective mechanisms Chaenomeles Common flowering Water based speciosa quince (FQ)

Chinese hamster ovary (CHO) cells

Psoralea corylifolia (L.)

Delta 3,2hydroxybakuchiol

Chinese hamster ovary (CHO) cells

Sesamum indicum

Estradiol and phytoestrogens

Tripterygium wilfordii Hook F Valeriana jatamansi

Tripchlorolide

Water based

Valerilactones A and B

Methanol based

Ethanol based

Peganum harmala

Clorgyline and the beta-carbolines.

Ginkgo biloba leaves

Ginkgo biloba extract (EGb 761)

Cajanuscajan (L.) Apigenin and Millsp. Luteolin

Water based

Turbinaria decurrens

Water based

Fucoidan

Mucuna Pruriens MP seed extract (MP)

Ethanol based

FQ reduced the loss of TH-IR neurons in the SN in MPTP-treated mice Delta 3,2-hydroxybakuchiol protected against MPTP-induced behavioral and histological lesions. Phytoestrogens exerted neuroprotective effects with less hormonal effects than estrogen.

Selective, potent DAT inhibitor; therefore, it inhibited MPTP uptake by dopaminergic neurons. Inhibiting MPTP uptake by monoamine transporters.

Restored dopamine transporter expression to control levels without increasing expression of estrogen receptors. Stimulated mRNA expression of In vivo (in rat Tripchloride rescued models) dopaminergic neurons from MPTP BDNF and increases survival of toxicity. dopaminergic neurons in the SN. Valerilactones A and B inhibited SH-SY5Y cells Valerilactones A and B exhibited potent neuroprotective effects MPTP uptake by DAT. against MPP+ induced neuronal cell death Polyphenols protected GT polyphenols had inhibitory effects DAT-pCDNA3on DAT, through which they blocked transfected Chinese dopaminergic neurons against Hamster Ovary MPTP-induced injury MPTP uptake. cells. Substances with a MAO inhibiting Beta-carbolines inhibited the Recombinant human activity can have a oxidation of MPTP by MAO-B and/or monoamine neuroprotective potential. MAO-A, preventing the formation of oxidase A and B toxic pyridinum cations. enzyme EGb761 treatment reduced MAO C-57 black mice/ EGb761 produced reversible Corpus striatum activity during MPTP toxicity. inhibition of both monoamine cells. oxidase (MAO) isoforms. EGb761 exerted a neuroprotective EGb 761 contributed to regulation of effect against MPTP neurotoxicity. copper homeostasis in the brain Apigenin or Luteolin treatment Adult male Swiss- Treatment with apigenin or albino mice/Corpus Luteolin improved locomotor increased the levels of TH and BDNF, striatum cells activity in mice and prevented while it reduced the level of glial MPTP induced reduction of TH-IR fibrillary acidic protein in the SN. cells. Fucoidan treatment increased Fucoidan increased TH protein levels C-57 black mice/ Corpus striatum antioxidants and DA levels in the and DA content in striatal neurons. cells. SN and corpus striatum. Adult male Swiss- MP seed extract protected MP seed extract recovered the albino mice/Corpus dopaminergic neurons from number of TH-IR cells, striatum cells PC12 cells

Camellia sinensis Camellia sinensis polyphenols extract

Induced the accumulation of autophagosomes and caused upregulation of LC3-II. Cannabinoids rescued Cannabinoids enhanced the dopaminergic cells from MPP+ metabolic viability of tyrosine cytotoxicity. hydroxylase immunoreactive (TH-IR) cells. Duzhong antagonized the loss of Amelioration of the ubiquitinstriatal neurotransmitters and proteasome system and attenuation dopaminergic neurons. of MPTP induced protease dysfunction. MYH inhibited both the loss of TH- MYH provided neuroprotection for positive neurons in the SN and the PC12 cells through enhancing reduction of the optical density of autophagy of neurotoxic filaments. TH-immunoreactive (TH-IR) fibers in the striatum.

Wang et al. [87]

Liu et al. [65]. Moldzio et al. [88].

Guo et al. [89].

Bae et al. [90] and Bae et al. [64].

Zhao et al. [29]. Zhao et al. [68].

Gelinas et al. [74].

Li et al. [26].

Xu et al. [91].

Pan et al. [69].

Herraiz et al. [66].

Rojas et al. [67]. Rojas et al. [92]. Patil et al. [93]

Meenakshi et al. [94] Yadav et al. [95]

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Table 4 (Continued) Plant

Extract or active constituents

Extract type

Target cells

Silybum marianum

Silymarin

Water based

C-57 black mice/ Corpus striatum cells.

Selaginella lepidophylla

Trehalose

Water based

C57BL/6J male mice/Corpus striatum cells.

Combined extracts of eight plants Gardenia jasminoides Ellis

Chuan Xiong Cha Tiao pulvis (CXCT)

Combined formula of 14 plants extracts

Jitai tablet (JTT)

C57BL/6J male mice/Corpus striatum cells. C57BL/6J male mice/Corpus striatum cells.

Geniposide

5. Unknown mechanisms Ajuga ciliata clerodane diterpenes Bunge

Water based

C57BL/6J male mice/Corpus striatum cells.

Methanol based

SHSY5Y cells

Valeriana jatamansi

Iridoids, jatadoids A and B

Methanol based

SH-SY5Y cells

Roots of Rubus parvifollus L

Suavissimoside R1

Ethanol based

Rat model mesencephalic culture

Findings

Possible mechanisms

neuroinflammation with an enhanced neurotrophic potential. Silymarin treatment at 50 and 100 mg/kg protected against MPTP induced dopaminergic neuronal loss. Trehalose showed a protective effect against MPTP induced damage of microvessels and endothelial cells.

Silymarin diminished the number of apoptotic cells and preserved dopamine levels in the nigrostriatal pathway. Trehalose prevented MPTP induced reduction of TH and DAT in the SN. It also suppressed MPTP induced microglial activation and astrocytic hypertrophy. CXCT improved motor deficits and Treatment with CXCT increased attenuated neurodegeneration in striatal dopamine content and MPTP treated mice. enhanced the activity of SOD. Geniposide exerted its Geniposide treatment restored TH-IR neuroprotective effect by neuronal numbers and reduced Bcl-2 enhancing growth factor signaling signaling and caspase 3 activation. and the reduction of apoptosis JTT alleviated MPTP induced JTT prevented MPTP induced behavioral impairment and increase of DA metabolism and neuronal apoptosis. attenuated the decrease of DAT and dopamine D2 receptors.

Clerodane diterpenes enhanced survival of MPTP treated SHSY5Y cells. Iridoids showed neuroprotective effects against MPTP toxicity. Suavissimoside R1 showed a potent neuroprotective activity against MPTP toxicity.

Animal studies reported anti-inflammatory effects for several plant extracts such as CI extract, which inhibits cyclooxygenase II enzyme and trehalose, an extract of Selaginella lepidophylla, which was proven to inhibit MPTP induced microglial activation [32,78]. Moreover, the extract of CI plant has been shown to exert a modulating effect over neuroinflammatory signaling pathways via inhibition of nuclear factor- Kappa-B (NF-kB), improving functional recovery and cellular transduction of dopaminergic neurons [32]. A summary of the neuroprotective effects of medicinal plants is presented in Fig. 1. 3. Summary of preclinical trials Several studies have investigated the role of natural plant extracts in protection against MPTP induced neurotoxicity and evaluated their potential as therapeutic agents for PD (Table 4). 4. Discussion These data expand the literature by providing a scheme for possible neuroprotective mechanisms against MPTP induced neurotoxicity, making these extracts strong candidates for neuroprotection against PD. Over the last decade, multiple agents targeting oxidative stress and caspase cleavage have been evaluated in human trials. However, most of them came to futility. For example: antioxidants such as coenzyme Q10, tocopherol, and mitoquionone and antiapoptotic agents such as TCH 346 and CEP1347 could not stop the progression of PD and did not provide any symptomatic benefits for PD patients [103–109]. These failures were mainly due to the methodological limitations of clinical trials' design and lack of knowledge about the primary PD pathology. Recent evidence suggests the involvement of oxidative stress,

The mechanism neuroprotective investigated. The mechanism neuroprotective investigated. The mechanism neuroprotective investigated.

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Sarkar et al. [78]

Shu et al. [97] Chen et al. [98]

Liu et al. [99]

of its effect is still to be

Guo et al. [100].

of their effect is still to be

Xu et al. [101].

of its effect is still to be

Yu et al. [102].

microglial activation, neuroinflammation, and apoptotic mechanisms in PD pathology [15]. However, it is not known exactly whether one or more of these pathologies initiate(s) the disease. Building upon this, medicinal plants and their extracts and active constituents working on multiple mechanisms, are strongly recommended neuroprotective agents for further clinical development. It should be mentioned that some of the explained mechanisms have not been introduced to the first in-human trials due to lack of pre-clinical evidence. Moreover, the accumulation of alphasynuclein particles is not reproduced in MPTP model; therefore, other PD models should be used to verify the effect of plant extracts on this pathological trait. In the list below, we highlighted some plant extracts with novel neuroprotective mechanisms to be confirmed in further experiments before moving to the first inhuman trials: (1.) The extract of Tripterygium wilfordii Hook F (Tripchlorolide) rescued dopaminergic neurons from MPTP toxicity by stimulating brain-derived neurotrophic factor (BDNF) mRNA expression and therefore, increasing survival of dopaminergic neurons in substantia nigra pars compacta. (2.) The extract of cruciferous vegetables (3H-1,2-dithiole-3thione) acted via increasing mRNA expression of the gamma-glutamylcysteine ligase catalytic subunit (GCLC), GR, and NQO1 in neuronal cells. (3.) The extract of Panax notoginseng (Panaxatriol saponins) could control the redox balance by inducing Thioredoxin-1 expression and inhibition of apoptosis. (4.) The extract of Radix Paeoniae Alba (Paeoniflorin) reduced cytosolic free calcium concentration and caused upregulation of LC3-II protein and overexpression of LAMP2A.

Please cite this article in press as: A.I. Abushouk, et al., Neuroprotective mechanisms of plant extracts against MPTP induced neurotoxicity: Future applications in Parkinson’s disease, Biomed Pharmacother (2016), http://dx.doi.org/10.1016/j.biopha.2016.11.074

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Moreover, preclinical trials described a neuroprotective potential for Ajuga ciliata Bunge extract (Clerodane diterpenes), root extract of Rubus parvifollus L (Suavissimoside R1), and Valeriana jatamansi extracts (Iridoids, jatadoids A and B). However, the mechanisms of their action have not been yet elucidated. The underlying mechanisms for these extracts should be addressed in future research. Finally, the promising therapeutic effects of plant extracts in neurodegenerative diseases should be advocated and shared with a wider community of researchers and practicing neurologists [110]. 5. Conclusion Several plants and their extracts showed neuroprotective effects against MPTP induced neurotoxicity, making them strong candidates for neuroprotection in PD. Multiple mechanisms for the same extract have been identified which allows researchers to target disease progression in different pathological stages and may be through multiple pathways. Further investigations are required to translate these neuroprotective mechanisms into safe and effective treatments for PD. Conflicts of interest None to declare. Funding source None to declare. References [1] L.M.L. De Lau, M.M.B. Breteler, Epidemiology of parkinson’s disease, Lancet Neurol. 5 (2006) 525–535. [2] M.G. Spillantini, M.L. Schmidt, Lee VM-Y, et al., a-Synuclein in lewy bodies, Nature 388 (1997) 839–840. [3] K.A. Jellinger, Pathology of parkinson’s disease, Mol. Chem. Neuropathol. 14 (1991) 153–197. [4] J.M. Savitt, V.L. Dawson, T.M. Dawson, Diagnosis and treatment of Parkinson disease: molecules to medicine, J. Clin. Invest. 116 (2006) 1744–1754. [5] A.M. Lazzarini, R.H. Myers, T.R. Zimmerman, et al., A clinical genetic study of Parkinson’s disease Evidence for dominant transmission, Neurology 44 (1994) 499. [6] D.M. Maraganore, M. De Andrade, T.G. Lesnick, et al., High-resolution wholegenome association study of Parkinson disease, Am. J. Hum. Genet. 77 (2005) 685–693. [7] M.H. Polymeropoulos, C. Lavedan, E. Leroy, et al., Mutation in the a-synuclein gene identified in families with Parkinson’s disease, Science 276 (1997) 2045–2047. [8] P.H. Weinreb, W. Zhen, A.W. Poon, et al., NACP, a protein implicated in Alzheimer’s disease and learning, is natively unfolded, Biochemistry 35 (1996) 13709–13715. [9] M.G. Spillantini, R.A. Crowther, R. Jakes, et al., a-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with Lewy bodies, Proc. Natl. Acad. Sci. 95 (1998) 6469–6473. [10] A.R. Winslow, C.-W. Chen, S. Corrochano, et al., a-Synuclein impairs macroautophagy: implications for Parkinson’s disease, J. Cell Biol. 190 (2010) 1023–1037. [11] Y. Mizuno, H. Mochizuki, N. Hattori, Alpha–synuclein, nigral degeneration and parkinsonism, Sci. Basis Treat. Parkinson’s Dis. (2005) 87–104. [12] T. Kitada, S. Asakawa, N. Hattori, et al., Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism, Nature 392 (1998) 605–608. [13] Y. Zhang, J. Gao, K.K.K. Chung, Parkin functions as an E2-dependent ubiquitin–protein ligase and promotes the degradation of the synaptic vesicle-associated protein, CDCrel-1, Proc. Natl. Acad. Sci. 97 (2000) 13354– 13359. [14] T.M. Dawson, V.L. Dawson, The role of parkin in familial and sporadic Parkinson’s disease, Mov. Disord. 25 (2010) S32–S39. [15] T. Pringsheim, N. Jette, A. Frolkis, T.D.L. Steeves, The prevalence of Parkinson’s disease: a systematic review and meta-analysis, Mov. Disord. 29 (2014) 1583–1590. [16] T.M. Dawson, V.L. Dawson, Molecular pathways of neurodegeneration in Parkinson’s disease, Science 302 (2003) 819–822. [17] N. Schmidt, B. Ferger, Neurochemical findings in the MPTP model of Parkinson’s disease, J. Neural Transm. 108 (2001) 1263–1282.

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