Traditional Medicine for Neuronal Health

By Bentham Science Publishers

Advances in the treatment of neurodegenerative diseases (NDs) are nominal. Currently available therapies are merely symptomatic treatments that cannot prevent the development of the disease. Several herbs have been found very useful for managing neurological diseases. There are immense possibilities to discover a more successful line of ND treatment. Phytochemicals from medicinal plants may play a vital role in maintaining the chemical balance of the brain by affecting the capacity of receptors for the major inhibitory neurotransmitters. A few plants have already gained popularity for the potential treatment of NDs. This volume highlights the therapeutic role of medicinal plants and their scientific validation for improving neuronal health. It presents 15 chapters that cover the herbal treatment of NDs, including Parkinson’s disease and Alzheimer’s disease. The contents cover a range of pharmaceutical agents like sirtuins, berberine, rosmarinic acid and resveratrol. The book serves as a reference for pharmacology and herbal medicine scholars as well as healthcare workers interested in information about alternative and complementary therapies for neurological disorders.

• Language: English
• Publisher: Bentham Science Publishers
• Release date: Sep 12, 2008
• ISBN: 9789815040197

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Parkinson's Disease: A Phytotherapeutic Prospective

Bhargab Deka¹, Bedanta Bhattacharjee¹, Naveen Shivavedi², Gireesh Kumar Singh³, Hans Raj Bhat¹, Surajit Kumar Ghosh¹, Anshul Shakya¹, *

¹ Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh-786004 (Assam), India

² Shri Ram Group of Institutions, Faculty of Pharmacy, Jabalpur-482002 (M.P.), India

³ Department of Pharmacy, Institute of Health Sciences, Central University of South Bihar, Gaya-824236 (Bihar), India

Abstract

Parkinson's disease (PD) is a complex multi-factorial, neurodegenerative disease characterized by neurodegeneration of dopaminergic neurons in the substantia nigra (SN) of the ventral midbrain area. Loss of dopamine (DA) supply induces an imbalance of multiple neurotransmitter networks in different parts of the brain. This contributes to many motor and non-motor symptoms in PD. The main goal of modern allopathic medicine is to restore DA function with synthetic levodopa (L-DOPA) and DA agonist, which has been partially effective; however, there are still several inadequacies and adverse effects that patients often cannot cope with. In the field of herbal medicine, extensive studies on bioactive phytocompounds have shown that it has immense potential as a neuroprotective therapy for neurodegenerative disorders, such as PD. Bioactive phytocompounds are very promising because they have minimal side effects and very high anti-inflammatory, anti-oxidant, and anticholinesterase activity. Recent preclinical studies suggest that several bioactive phytocompounds can be developed into pharmaceutical formulations for the treatment of PD. Ayurvedic medicines have been used in many countries and particularly in India since ancient times to prevent or cure PD. This article focuses on the recent evidence-based neuroprotective activity of medicinal plants like Mucuna pruriens, Curcuma longa, Zingiber officinale, Bacopa monnieri, Nardostachys jatamansi, Withania somnifera, and Silybum marianum in in vivo and in vitro PD research models.

Keywords: Ayurvedic medicine, Levodopa, Neurodegeneration, Parkinson’s disease, Phytotherapy.

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* Corresponding author Anshul Shakya: Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh-786004 (Assam), India; E-mail: [e-mail]

INTRODUCTION

Parkinson's disease (PD) is the most common type of progressive neurodegenerative disease, causes severe impairment, and impacts the quality of life [1]. It affects approximately 10 million people worldwide, and the prevalence in India is roughly 10% of the global burden. The most common cause of PD in older adults is idiopathic PD, also known as sporadic PD [2]. PD is typically related to motor symptoms, including tremors, akinesia/bradykinesia, reduced body balance, and rigidity. PD leads to neurodegeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), which is related to dopamine (DA) deficiency in basal ganglia. The most commonly recognized causes of PD are protein misfolding, aggregation, toxicity, mitochondrial dysfunction, and oxidative stress [3-5].

Protein misfolding, mainly alpha-synuclein (α-syn), is critically linked to PD. The small protein α-syn consisting of 140 amino acids is present in the brain and other organs, like the heart and gut [6]. The role of this protein in humans is still unclear; however, studies have shown that α-syn plays normal physiological roles, such as storage, recycling, and compartmentalization [7]. There are two very well-known hypotheses of α-syn misfolding, i.e., exposure to environmental toxins and heavy metals [8], and another is misfolding due to dysbiosis of the microbiome of the gut [9].

For metabolic requirements, neurons are largely dependent on mitochondrial integrity. Effective transport of mitochondria to the hot spots of energy demand is required, such as pre-synaptic and post-synaptic areas. It is, therefore, not shocking that mitochondrial dysfunction will promote neuronal breakdown and degeneration [10]. The generation of cellular energy (ATP) is formed in five transmembrane complexes after electron transportation in the mitochondrial membrane [11]. In this process, the electrons leak out of the chain, mainly from complexes I and III, and react with oxygen to form a superoxide ion (O2-). O2- production occurs at minimum levels under normal physiological conditions; however, dysfunction of complex I and III contributes to elevated O2- generation, and may be one of the main hallmarks of neurodegeneration in SNpc of patients with PD [12, 13].

Since ancient times, PD has been known in different parts of the world. Asian countries like India, Japan, Korea, and China, which have a treasure of traditional systems of medicine, have been using different plant-based medications to treat PD for a long time [14]. In India, the Ayurvedic system of medicine is the oldest form of an alternative and holistic medicinal system. PD is described as Kampavata in Ayurveda. The formulation prepared from seeds of Mucuna pruriens has been prescribed by Ayurveda to treat symptoms that are the hallmark of PD. Scientific investigations showed that M. pruriens is used to treat long-term improvement in PD. In clinical trials, powdered seed formulation of M. pruriens has also shown positive effects with accelerated action in PD patients [15].

Long-term therapeutic and health-promising properties of bioactive phytochemicals from medicinal plants have drawn the interest of the scientific community for the prevention or treatment of different types of chronic and disabling neurological disorders [16-19]. Therefore, scientific examination and validation of these bioactive phytocompounds on preclinical models are very valuable for the development of neuroprotective drugs. The use of bioactive phytocompounds for these types of chronic and progressive disorders may yield more satisfactory clinical outcomes than synthetic chemical drugs [20-22].

NEUROPROTECTIVE ACTIVITY OF BIOACTIVE PHYTOCOMPOUNDS FROM MEDICINAL PLANTS

M. pruriens (Kauncha)

M. pruriens belongs to the Fabaceae family, and the subfamily Papilionaceae is commonly distributed in the tropical and subtropical regions of the world, characterized by 150 species of annual and perennial legumes. Among these different varieties of wild legumes, only velvet beans (M. pruriens) are used for a range of medicinal purposes [23, 24].

Plant Description

The plant is a perennial, long-grown, climbing shrub that can reach more than 15 m in length. When the plant is young, it is almost entirely covered with shaggy hair, but when it is older, it is almost fully hair-free. The leaves are tripinnate, ovate, inverted, rhombus-shaped, or broadly ovate [25].

Phytoconstituents of M. pruriens

Phytoanalytical screening of velvet beans has been found to have 3-(3,4- dihydroxy phenyl)-l-alanine or levodopa (L-DOPA) and can be used to alleviate motor symptoms of PD [26]. It also contains glutathione (GSH), gallic acid (GA), and beta-sitosterol. It has unspecified bases, such as mucunine, mucunadine, prurienine, and prurienine. Serotonin is found in pods as well. Seeds also include palmitic, stearic, oleic, and linoleic acid oils [27].

Neuroprotective Activity of M. pruriens in Parkinson’s Pathology

In 1973, the first extraction of L-DOPA from M. pruriens seeds was achieved, and they were recognized as a significant source of L-DOPA for treating PD [28]. The effectiveness of M. pruriens was shown by Katzenschlager et al. in 2004 by contrasting it with the normal drug combination, L-DOPA/ carbidopa (C-DOPA). At weekly intervals, patients were administered single doses of 200/50 mg L-DOPA/ C-DOPA and 15 g and 30 g of M. pruriens preparation in randomized order. The pharmacokinetics of L-DOPA was calculated, and the Unified PD Rating Scale and tapping speed were obtained at baseline and consistently during the 4 h after ingestion of the medication. Without worsening dyskinesia, M. pruriens acted quicker and lasted longer than L-DOPA/ C-DOPA [29]. Nagashayana et al. demonstrated a prospective clinical study where patients were divided into two separate groups, one receiving treatment consisting of a mixture of powders of M. pruriens (4.5 g), Hyoscyamus niger (0.75 g) seeds, Withania somnifera (14.5 g), and Sida cordifolia (14.5 g) roots in 200 mL cow’s milk, and other receiving palliative therapy. The group that received phytoingredients had shown better improvement in tremors, bradykinesia, stiffness, and cramps as compared to the group that underwent only palliative therapy [30].

Cilia et al. have shown a clinical study in which 18 patients with advanced PD obtained the following randomized treatments: (a) dispersible L-DOPA at 3.5 mg/kg integrated with the standard benserazide DOPA-decarboxylase inhibitor; (b) high-dose M. pruriens (17.5 mg/kg); (c) low-dose M. pruriens (12.5 mg/kg); (d) pharmaceutical preparation of L-DOPA without DOPA-decarboxylase. They observed that a single low dose of M. pruriens exhibited comparable effectiveness to a mixture of L-DOPA/C-DOPA with fewer dyskinesias [31].

A preclinical study in which a Parkinsonian rat model was developed by intra-striatal injection of 6-hydroxydopamine (6-OHDA) with amphetamine was demonstrated by Ghazala et al. They compared synthetic L-DOPA (2.5 or 5.0 g/kg) with endocarp M. pruriens and found that extract M. pruriens was more effective than that of synthetic L-DOPA [32].

Curcuma longa (Turmeric)

C. longa is a member of the family of ginger (Zingiberaceae). Indian turmeric is very common compared to other countries due to the high content of curcumin. Rhizomes from C. longa are widely recognized as Haldi or turmeric. It is widely used for the treatment of various illnesses, viz. gastrointestinal diseases, especially for the biliary and hepatic disorders, diabetic wounds, rheumatism, infections, inflammation, sinusitis, anorexia, coryza, and cough by traditional medical practitioners of the Ayurvedic system of medicine, and also it is very commonly used for culinary purposes in Indian standard diet [33].

Plant Description

Turmeric is a rhizome with a rootstock that possesses broadly lanceolate or oblong leaves with deep purple ferruginous. Its petiole and sheath are long. It involves a spike that emerges in front of the branches, and a flowering green bract with a ferruginous tinge, light yellow flower, and reddish outer lip [34].

Phytoconstituents of Turmeric

Curcumin, demethoxycurcumin, and bisdemethoxycurcumin are the major phenolic compounds in turmeric, commonly recognized as curcuminoids (3-6%). They are responsible for the neuroprotective activities of turmeric [35]. In the 19th century, the primary coloring principle of the turmeric rhizome was isolated and named curcumin. Its chemical composition has been determined by Roughley and Whiting. Turmeric contains protein (6.3%), fat (5.1%), minerals (3.5%), carbohydrates (69.4%), and moisture (69.4%). (13.1%). Phenolic diketone, curcumin (diferuloylmethane) (3-4%), is responsible for the yellow color and consists of curcumin I (94%), curcumin II (6%), curcumin III (0.3%), and volatile oil (4.2%). Turmerone, ar-turmerone, curcumene, germacrone, and ar-curcumene are the primary components. Copper, zinc, campesterol, stigmasterol, beta-sitosterol, fatty acids, potassium, sodium magnesium, calcium, manganese, and iron are other chemical compounds [36].

Neuroprotective Activity of Curcumin in Parkinson’s Pathology

In humans, α-syn is a protein encoded by the SNCA gene. People with PD are found to have abnormal clumps of misfolded α-syn called Lewy bodies (LB), which are toxic to brain cells. It is abundant in the brain but is also present significantly in the muscles of the heart, intestines, and other tissues. Abnormal clusters of α-syn have also been found in the intestines of people with PD. Researchers have suggested that α-syn may potentially misfold and accumulate in the gut. Recent studies have shown that α-syn clumps can misfold nearby normal α-syn proteins, and trigger further clumps. These results indicate that a chain reaction triggered by misfolded α-syn could migrate from the intestine to the vagus nerve, which directly affects the brain [37].

The effect of curcumin solution (5 μL) on α-syn protein aggregation was explored by Pandey et al. An in vitro model was developed where the aggregation of α-syn was accomplished by treatment of purified α-syn protein (wild-type) with 1 mM Fe³+ (Fenton reaction). They observed that curcumin therapy inhibited α-syn aggregation in a dose-dependent manner and also improved the solubility of α-syn. They also tested the same in a cell line-based culture using the catecholaminergic cell line SH-SY5Y. It was observed that after 48 h of subsequent curcumin addition, it decreased the aggregation of mutant α-syn by 32% [38, 39].

The effect of curcumin in soybean oil (incorporated into the diet) on the motor activity of the transgenic mice model, which overexpresses wild-type human tagged α-syn protein, was investigated by Spinelli et al. They observed that curcumin diet intervention significantly improved gait impairments and contributed to an improvement in phosphorylated forms of α-syn at the cortical presynaptic terminals [40]. An experiment was carried out by Pan et al. to assess curcumin's efficacy to prevent nigrostriatal neuronal degeneration in a 1-methyl 4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) model. It was shown that curcumin (50 mg/kg/day) inhibits nigrostriatal neuron degeneration by inhibiting mitochondrial dysfunction and by suppressing the hyperphosphorylation of c-Jun N-terminal kinase (JNK) caused by MPTP [41].

Zingiber officinale (Ginger)

Ginger is a well-known herb native to India, a common ingredient found in every Indian kitchen for culinary purposes. It is used in dishes, such as curries, desserts, cakes, and biscuits, as a flavoring agent. Ginger is a popular herbal remedy used in the traditional medicine system for treating different ailments. Many of the pharmacological effects of ginger include anti-emetic, anti-diabetic, analgesic, anti-arthritis, anti-cancer, anti-oxidant, anti-ulcer, anti-microbial, anti-inflammatory, immunomodulatory, and cardiovascular function [42].

Plant Description

In the Zingiberaceae family, ginger is an upright herbaceous perennial plant cultivated for its edible rhizome (underground stem). The rhizome is brown, corky in the outer layer, and light yellow in the center. With linear leaves arranged alternately on the stem, the above-ground shoot is erect and reed-like. The shoots come from multiple bases, circling each other. The leaves can be 2.75 inches (7 cm) long and 0.7 inches (1.9 cm) wide. On shorter stems, the floral heads are borne, and the plant produces cone-shaped light yellow flowers. The ginger plant is grown as an annual plant and can reach a height of 0.6-1.2 m (2-4 ft) [43, 44].

Phytoconstituents of Ginger

The main active ingredients in ginger, such as zingerone, gingerdiol, zingiberene, gingerols, and shogaols, are known to have an antioxidant function [45]. In several studies in the past, the shagaols have shown very strong neuroprotective activity against PD. The principal antioxidant of ginger was proved to be 6-gingerol, and its derivatives contained volatile oils, shogaols, diarylheptanoids, gingerols, paradol, zerumbone, 1-dehydro- [10] gingerdi-one, terpenoids, and ginger flavonoids. Ginger pungency is due to the presence of volatile oils, non-volatile compounds, and oleoresins. In the fresh ginger rhizome, gingerols have been established as the main active ingredients, and gingerol [5-hydroxy-1-(4-hydroxy-3-methoxy phenyl) decane-3-one] is the most abundant component in the gingerol sequence [46]. Ginger dramatically reduced lipid peroxidation (LPO) by preserving the activity of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX), in the rat [47].

Neuroprotective Activity of Ginger in Parkinson’s Pathology

Park et al. presented a preclinical experiment in which cultured mesencephalic rat cells were treated for one hour with 6-shagaol (10 mg/kg/day) and then for another 23 h with 1-methyl-4-phenylpyridium (MPP+). 6-shogaol significantly increased the number of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in MPP+ treated rat mesencephalic cultures and reduced the levels of tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO). Treatment in mice with 6-shogaol reversed MPTP-induced motor control alterations and bradykinesia. In addition, 6-shogaol reversed TH-positive cell count in the SNpc and TH-IR fiber density in the striatum (ST) caused by MPTP [48]. Another experiment where ginger rhizome extract (600 mg/kg) was administered to rats was shown by Hussein et al. They suggested that ginger may be a neuroprotective agent due to the presence of polyphenolic compounds that can reduce the neurotoxic impact of monosodium glutamate through altering neurotransmitter levels and preventing the aggregation of 8-hydroxy-2'-deoxyguanosine (8-OHdg) and amyloid. This study has claimed that ginger improves the histological characteristics of the brain and attributes this effect to the antioxidant properties of ginger [49].

A study carried out by Ha et al. has demonstrated 6-shogaol to block LPS-induced microglial activation both in the primary cortical neuron-glia culture and in the in vivo neuroinflammatory model. Also, 6-shogaol has been proven to have important neuroprotective effects in vivo in transient global ischemia by inhibition of microglia. These findings indicate that 6-shogaol is an important therapeutic agent for the treatment of neurodegenerative diseases [50-53].

Bacopa monnieri (Brahmi)

B. monnieri, also popularly known as Brahmi, is a plant traditionally used in the Ayurvedic system of medicine for treating different forms of neurological conditions. To enhance cognitive functions, it has been widely used as a nootropic agent and is more commonly defined as a brain tonic. This increases brain perfusion, leading to the improvement of general neurological functions. Brahmi has strong anti-oxidants, and is used for neuroprotection. For example, Brahmi is used to promote neuronal activity in neurodegenerative diseases, including PD, mediated by oxidative stress [54, 55].

1.2.4.1. Plant Description

B. monnieri, sometimes referred to as water hyssop, belongs to the family of Scrophulariaceae. It is a spreading, semi-succulent herb that occurs mainly in the Indian subcontinent, Southeast Asia, Australia, the subtropical United States, and tropical Africa in marshy wetlands at an altitude of 1500 m. The leaves of B. monnieri are normally oblong in shape or spatulate, thick with light purple or white flowers [56, 57].

Phytoconstituents of Brahmi

Chemicals with complex structures, primarily triterpenoid saponins named jujubacogenin, bacosides, and psudojubacogenin glycosides, were characterized and isolated from B. monnieri. There are about 12 structural analogs in the family of bacosides that have been recognized till now. A distinct class of saponins was described and named as the sequence of compounds I to XIII in a recent study [58]. Bacoside A, Bacoside B, Bacopa saponins, D-mannitol, and monnieri sides I to III are important among the other bacoside saponins. B. monnieri has numerous pharmacological effects, mostly due to the presence of triterpenoids, saponins, and bacosides, which are widely accepted. Bacoside A is the most widely studied bioactive component, consisting of bacoside A3, bacosaponine C, bacopaside II, and bacoside X. Several chemical constituents are also present in the B. monnieri extract, such as brahminic acid, beta acid, betulinic acid, wogonin, brahamoside, oroxinide, brahminoside, isobrahmic acid, stigmasterol, and b-sitosterol [59].

Neuroprotective Activity of Brahmi in Parkinson’s Pathology

To relieve different symptoms of PD, Brahmi extract has been used since ancient times. In various animal models, including cell lines, Drosophila, zebrafish, and rodents, environmental toxin-induced (ROT, PQ, MPTP) and genetic forms (PINK 1) were successfully used to mimic behavioral and physiological symptoms of PD [60]. It is worth remembering that B. monnieri has an essential degree of anti-oxidant activity, which is why most studies have recorded its mode of action in PD by alleviating the pathways of oxidative stress [51]. Some influential studies are mentioned in Tables 1 and 2.

Table 1 B. monnieri extract results in the stabilization of motor and non-motor symptoms of PD in mouse models and cell lines using toxic environmental compounds.

Nardostachys jatamansi (Jatamansi)

N. jatamansi is a small dwarf plant found in Alpine Himalayas belonging to the family Valerianacae. Jatamansi has a very long history. It is being used in traditional and alternative medicine since ancient times. Jatamansi exhibits different kinds of pharmacological activities, such as anti-fungal, hepatoprotective, CNS activity (enhancement in production of neurotransmitters), anti-oxidant, anti-convulsant, anti-diabetic, and anti-Parkinsonian [67].

Plant Description

It is a small, perennial, dwarf, hairy, herbaceous, and rhizomatous plant. The leaves, in dense cymes, are rosy, softly pink or blue. The rhizomes have a dark grey appearance and are crowned with reddish-brown tufted fibers. The odor is highly agreeable and aromatic. The thickness of the rhizomes is 2.5-7.5 cm in height. The shape is cylindrical and elongated [68, 69].

Phytoconstituents of Jatamansi

The plant's rhizomes and roots are of medicinal significance and have been the key subject of phytochemical studies as well. Both volatile and non-volatile components are produced by N. jatamansi. A significant portion of volatile compounds is formed by sesquiterpenes, while the main components of non-volatile extracts are sesquiterpenes, coumarins, lignans, neolignans, and alkaloids. The chemical test conducted by Chatterjee et al. revealed a new terpenoid ester, nardo-stachysine [70]. Sesquiterpenes are present in high amounts and are responsible for the essential oil in the roots of the plant. The major sesquiterpenes present in the jatamansi plant are jatamansone or valeranone. Alpha-patcho-ulense, angelicin, β-eudesem, β-atchoulense, β-sitosterol, calarene, elemol, jatamansin, and jatamansinol are also known as sesquiterpenes [71, 72]. A new sesquiterpene aldehyde, called nardal, was reported from the jatamansi plant [73].

Neuroprotective Activity of N. jatamansi in Parkinson’s Pathology

Ahmad et al. conducted a study in which 6-OHDA-treated rat models were developed. Rats were treated with 200, 400, and 600 mg/kg body weight of N. jatamansi root extract for three weeks. On day 21, 2 μL of 6-OHDA (12 μg in 0.01% ascorbic acid-saline) was infused into the right ST, while 2 μL of the vehicle was infused into the sham-operated group. Three weeks after the 6-OHDA administration, the results were very promising. Due to 6-OHDA injections, the loss of locomotor activity and muscle coordination was significantly and dose-dependently restored by N. jatamansi extract. The lesions due to LPO and significant depletion of the reduced GSH content in SN were also prevented by N. jatamansi. A significant decrease in the level of DA and its metabolites and an increase in the number of DA D2 receptors in the ST have also been found with the treatment of N. jatamansi. There is also evidence of increased density of TH-IR fiber in the ipsilateral ST of the lesioned rats following treatment with N. jatamansi. The data indicate that the jatamansi extract could help reverse the damage caused by Parkinsonism [77].

W. somnifera (Ashwagandha)

W. somnifera is popularly known as Indian ginseng or Indian winter cherry. It is generally referred to as Ashwagandha because it smells like horse urine. Horse means Ashwa and gandha means odor. It is commonly used in Ayurveda for the treatment of stress, anxiety, arthritis, and other CNS diseases, such as PD and Alzheimer's disease. It is claimed to be an effective neuronal tonic in Ayurveda [74, 75].

Plant Description

W. somnifera is a small 2 m tall and 1 m wide shrub. The short, fine silver-grey, branched hair covers almost the whole plant. The stems below are brownish, prostrate to erect, and often without leaves. The leaves are alternating (opposite to the flowering shoots), simple, complete to slightly wavy, narrowly ovate, obviate or oblong, 30-80 mm long and 20-50 mm high, narrow to 5-20 mm long, almost hairless, and green above, densely hairy below, and narrow to 5-20 mm long [76, 77].

Phytoconstituents of Ashwagandha

Through laboratory study, 35 chemical constituents have been identified. Roots of W. somnifera primarily consist of compounds known as withanolides, which are believed to be responsible for their excellent medicinal properties. Withanolides are steroidal, and have similarities with the active constituents of Asian ginseng (Panax ginseng), known as ginsenosides, both in their action and appearance [78-80]. Alkaloids, isopelletierine, anaferine, cuseohygrine, anahygrine, etc., and steroidal lactones, such as withanolides and withaferins, are bioactive chemical constituents of W. somnifera. Sitoindoside VII and VIII and withanolides with a glucose moiety of carbon 27 sitoindoside IX and X are other chemical constituents of W. somnifera. Seven new withanolide glycosides I to VII were isolated and described in 2001 by Matsuda et al. [81, 82].

Neuroprotective Activity of Ashwagandha in Parkinson’s Pathology

The production of oxidative free radicals involved in the process of neurodegenerative diseases, such as PD, is increased by compromised anti-oxidative defense mechanisms. Several major free radical enzyme scavenging systems, such as SOD, CAT, and GPX, are present throughout the body [83]. A defect in the activity of these enzyme processes contributes to the accumulation of toxic free radicals and the consequent degeneration of cells and tissues [84].

Manjunath et al., in 2015, conducted a study to check the neuro-ameliorative effects of W. somnifera in the ROT D. melanogaster model (Oregon-K). They found significant evidence of protection against ROT-induced lethality, and the survivor flies showed significant improvement in locomotor function. Further, biochemical analysis revealed that W. somnifera significantly reduced ROT-induced oxidative stress [84, 85]. Further analysis revealed W. somnifera extract to substantially reverse dose-dependent levels of reduced GSH, GPX, SOD, and CAT compared to the 6-OHDA rat model [86]. Prakash et al., in a PD mice model, investigated the neuroprotective function of W. somnifera extract against DAergic neurodegeneration caused by Maneb-Paraquat (MB-PQ). Important evidence has been obtained that it is capable of inhibiting oxidative stress in nigrostriatal tissues and simultaneously increasing the number of positive TH cells in the SN area of the MB-PQ-mediated brain in the PD mice model [70].

Silybum marianum (Silymarin)

Silymarin is a flavonoid originating from a plant belonging to the Asteraceae/Compositae family, S. marianum. As the leaves of the plant have milky veins, it is commonly known as milk thistle. Silymarin is used mostly as a hepatoprotective agent and for gall bladder disorders. But it has some impressive neuroprotective properties aside from this, which can be used with neurodegenerative disorders, such as PD. The wide pharmacological role of silymarin is primarily due to its excellent antioxidant properties [87].

Plant Description

S. marianum is a rosette-forming biennial native to the Mediterranean region, generally referred to as the Blessed Thistle or Milk Thistle (Southern Europe, Western Asia, and Northern Africa). In the first year, a showy rosette of highly lobed, obviate, spiny green (up to 20' long) leaves with distinctive white marbling occurs. When sliced, the leaves and stems exude a milky sap, which is the common term for milk thistle. In the second year, from the foliage rosette, a large flower stalk rises to 3-5' tall, bearing thistle-like, deeply scented, purple-pink (2' across) flower heads underpinned by spiny bracts. As the plant has finished its biennial life, flowers are replaced by seeds [88, 89].

Phytoconstituets of Silymarin

The main bioactive phytochemical of silymarin is silybin, constituting more than 50% of the composition. Silychristin, silydianin, and isosilybin are also present as other flavonolignans along with some unidentified polymers. Quercetin, taxifolin, and kaemferol are present in minor quantities. Silymarin's composition depends on the variety of S. marianum and the state in which it was cultivated. Since it significantly affects biological activities, the technique of plant tissue culture is considered to be the better alternative to enhancing the silymarin content. With distinct regulators, cultural dynamics can be manipulated [90].

Neuroprotective Activity of Silymarin in Parkinson’s Pathology

Silymarin, which has significant antioxidant effects, is a polyphenolic flavonoid. Its major functions are free radical scavenging, raising the level of cellular GSH, and enhancing SOD activity. Since oxidative stress is one of the key triggers of neurodegenerative processes, the use of silymarin in PD treatment can be very promising [91].

In a study, silymarin has been reported to inhibit the activation of microglia as well as the synthesis of inflammatory mediators, such as a product of TNF-α and NO, reducing damage to DAergic neurons [92]. As reported, by decreasing apoptosis in the SN and preserving DAergic neurons, silymarin maintained striatal DA levels. The anti-oxidant and anti-inflammatory functions of silymarin are the reasons for these effects [93].

In the study by Singhal et al., silymarin (40 mg/Kg) and melatonin (30 mg/Kg) were found to protect against midbrain DAergic neuronal loss and associated behavioral impairments in MB-PQ-induced animal PD models [94].

An in vitro study indicated that silymarin guards against neurotoxicity caused by lipopolysaccharide (LPS) by inhibiting microglia activation, indicating its anti-inflammatory behaviour [95]. Similar in vitro experiments have shown that silymarin dissolved in dimethyl sulfoxide (DMSO) also reduces the production of superoxide and TNF-α, thus inhibiting inducible NO synthase (iNOS) [96].

In vivo PD models have shown that silymarin (100 mg/kg) in MPTP-intoxicated mice reduces apoptosis in SN, protects DAergic neurons, and thus regulates striatal DA levels [97]. Another in vivo study demonstrated that silymarin (200 mg/kg) binds to estrogen receptors β in the CNS region, and it attenuates toxin-induced neurotoxicity, inhibits LPO, and works synergistically with antioxidants, such as GSH [98, 99].

Table 2 Summary of beneficial effects of different plants on in vitro and in vivo models of Parkinsonism.

CONCLUSION

PD is multifactorial and has many pathological mechanisms of neurodegeneration. Till today, there are no modern allopathic drugs that have disease-modifying effects and that can target a specific pathomechanism. On the other side, plant extracts are known to have many bioactive phytochemicals that possess different kinds of biological or pharmacological effects. This combination of bioactive phytochemicals might target different molecular pathomechanisms in neurodegenerative disorders, for instance, PD. Recently, the scientific community has developed a sufficient interest in the isolation, identification, and characterization of bioactive phytochemicals to cure PD. Traditionally, these bioactive phytochemicals have been used for the treatment of CNS-related disorders, but still lack their quality control data and safety in consumption across the population, which limits their use in the modern world of medicines. Although, many bioactive compounds from natural sources have recently been documented to have neuroprotective effects in different laboratories. PD models from ethnobotanical and ethnopharmaceutical resources, large-scale, double-blind, and placebo-controlled studies, and their pharmacokinetic evidence are needed to determine the dosage type and also assess the therapeutic impact of bioactive phytocompounds on PD. Here, we have surveyed the literature for the most relevant available evidence on bioactive constituents from natural sources possessing neuroprotective function in different laboratories of PD models. Although the spectrum of these studies reported is not comprehensive, all the bioactive compounds listed have shown a major neuroprotective impact on PD models. Hence, these bioactive phytocompounds can be a promising source for the treatment of PD.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENT

The authors thank the LNB Library, Dibrugarh University, Assam, India, for providing the facilities required to access relevant papers.

REFERENCES