Indopathy for Neuroprotection: Recent Advances

Globalizing Traditional Knowledge of Indian Medicine: Evidence-based Therapeutics

Hagera Dilnashin¹, *, Hareram Birla¹, Chetan Keswani¹, Surya Pratap Singh¹, *

¹ Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005 (U.P.), India

Abstract

With the advent of modern medicine, the use of medicinal plants is an ancient therapeutic strategy used by traditional healers and is very useful in traditional medicine. Medicinal plants are compatible with human physiology, which has been adapted for centuries.

Keywords: Indopathy, Medicinal plants, Therapeutic strategy, Therapeutics, Traditional medicine.

* Corresponding authors Hagera Dilnashin and Surya Pratap Singh: Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi-221005 (U.P.), India; E-mails: hagera.dilnashin10@bhu.ac.in and suryasinghbhu16@gmail.com

INTRODUCTION

In today's scenario, scientists need to focus on finding the compounds of herbs involved in the cure, alleviation, and cure of the disease. Traditional medicine includes long-term treatments that people inherit and practice to prevent and treat illness. Plants have formed the basis of traditional medicinal systems. It consists of several medicinal systems from different parts of the world, which include Chinese herbal medicine (China), Indian herbal medicine (India), Kampo medicine (Japan), Native American medicine (US), Tibetan medicine (Tibetan), Jamu Genndong (Indonesia), traditional African medicine (Africa), and traditional Hawaiian medicine (Hawaii) [1, 2].

India has an ancient heritage of traditional medicine. Materia medica of India provides a wealth of information on the folklore practices and traditional aspects of therapeutically important natural products. Each of these traditional systems has unique aspects, but there is a common thread among their fundamental principles and practices in the use of natural products, mostly herbs [3-5].

Indopathy is a traditional Indian medicinal system that includes Ayurveda, Yoga, and Naturopathy, Unani, Siddha, and Homeopathy (AYUSH). It is a well-known medication system because of its various pharmacological effects that are beneficial to human health [6]. In addition to its strong neuroprotective potential, many studies have also described the significant therapeutic effects of herbal medicine against several central nervous system diseases [4, 7-9]. The biological effects of herbal plants have been generally attributed to ancient science's major protective effect. The results of studies with different mechanisms indicate the neuroprotective effects of plants, most of which mention positive effects on oxidative stress and other assessment parameters [5, 10-13]. The modulatory role of the alternative medicinal system will not only bring new drug discoveries [14] but also treat central nervous system diseases and help understand the complex pathophysiology of neurodegenerative diseases [3, 15-18].

CONCLUSION

Over time, Indopathy has been tested, and people have used it for their medical care for a long time. Before British rule, these were the main treatments in India but later changed under the influence of western culture. So Indopathy are well-rooted with a profound clinical basis, where scientific validation is sometimes the major constraint for their development. Despite these setbacks, Indopathy remains in India and continues to grow in the global market [19]. As the Western world pays more and more attention to herbal drugs, especially Indopathy, it is necessary to examine these systems and take appropriate measures to restore the concept of traditional medicine as the main therapeutic medicinal system [20, 21].

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The author declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

Naturally-occurring Bioactive Molecules with Anti-Parkinson Disease Potential

Atul Kabra¹, *, Kamal Uddin², Rohit Sharma³, Ruchika Kabra¹, Raffaele Capasso⁴, Caridad Ivette Fernandez Verdecia⁵, Christophe Hano⁶, *, Natália Cruz-Martins⁷, ⁸, ⁹, *, Uttam Singh Baghel¹⁰, *

¹ School of Pharmacy, Raffles University, Neemrana, Alwar-301020 (Rajasthan), India

² Aligarh College of Pharmacy, Aligarh-202002 (U.P), India

³ Department of Rasa Shastra and Bhaishjya Kalpana, Faculty of Ayurveda, IMS, Banaras Hindu University, Varanasi, 221005 (U.P), India

⁴ Universita Degli Studi di Napoli Federico II, Naples, Italy

⁵ International Center of Neurological Restoration (CIREN), Basic Division, La Habana, Cuba

⁶ Laboratoire de Biologie des Ligneux et des Grandes Cultures, INRAUSC 1328, Université d’ Orléans, 45100 Orléans, France

⁷ Faculty of Medicine, University of Porto, Porto, Portugal

⁸ Institute for Research and Innovation in Health (i3S), University of Porto, Porto, Portugal

⁹ Institute of Research and Advanced Training in Health Sciences and Technologies (CESPU), Rua Central de Gandra, 1317, 4585-116 Gandra PRD, Portugal

¹⁰ Department of Pharmacy, University of Kota, Kota-324005 (Rajasthan), India

Abstract

Parkinson's disease (PD) is a complex limiting neurodegenerative disorder, with a rising incidence. Current therapeutic options for PD have multiple limitations, and naturally occurring biomolecules, often known as phytochemicals, with potent neuroprotective activities, have been searched to meet the need. Thus, this chapter encompasses in-depth information on reported anti-PD activities of medicinal plants in light of available pre-clinical and clinical studies and shares the mechanisms of action proposed in fighting PD. Published information from PubMed, Scopus, Science Direct, Springer, Google Scholar, and other allied databases was analyzed. There is rising interest among researchers in investigating medicinal plants and their isolated compounds for their anti-PD efficacy. Scattered information about the anti-PD potential of plants and bioactive compounds is reported in the scientific domain. A total of 92 medicinal plants belonging to 63 families, exhibiting anti-PD activity were

discussed. Botanical species have revealed an extreme potential, encouraging future examination. Data discussed here can be used for further research and clinical purposes.

Keywords: Bioactive molecules, Dopamine, Lewy bodies, Medicinal plant extracts, Parkinson's disease, Substantia nigra.

* Corresponding authors Atul Kabra, Christophe Hano, Natália Cruz-Martins & Uttam Singh Baghel: School of Pharmacy, Raffles University, Neemrana, Alwar-301020 (Rajasthan), India, Laboratoire de Biologie des Ligneux et des Grandes Cultures, INRAUSC1328, Universitéd’Orléans, 45100 Orléans, France, Faculty of Medicine, University of Porto, Porto, Portugal & Department of Pharmacy, University of Kota, Kota-324005 (Rajasthan), India; E-mails: ruchika.p88@gmail.com, drusb1985@yahoo.com, ncmartins@med.up.pt & hano@univ-orleans.fr

INTRODUCTION

Despite presenting a pathological mark of slowness, the manifestation and progression of Parkinson’s Disease (PD) are insinuated [1], featured by the progressive loss of dopaminergic neurons in the pars compacta of substantia nigra and by the decline in dopamine levels in the basal ganglia striatum [2, 3]. Consequently, the cholinergic neurons’ activity becomes comparatively dominant, while the nigrostriatal dopaminergic neuronal activity is decreased, which results in the advancement of movement disorder [4-6]. In the human system, PD is categorized by symptoms of motor neurons, viz. bradykinesia, resting tremors, rigidity, and postural instability [7], besides non-motor manifestations, such as neuropsychiatric abnormalities, disturbed sleep, dysautonomia, gastrointestinal disturbances, and sensory problems [8-12].

At the molecular level, although the pathophysiology of the disease still remains unclear, several pathways have been proposed to be involved in dopaminergic neuronal death, such as 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 through c-Abl activation [1, 13-15]. In this context, environmental factors, like permethrin pesticide exposure during brain development, have been associated with genetic and epigenetic changes leading to PD in rats, as well as in their untreated offspring (Fig. 1) [16-19].

For several decades, the therapeutic gold standard for PD has been based on the use of levodopa, in combination with a peripheral decarboxylase inhibitor. However, the long-term use of these drugs often leads to multiple secondary effects, including gastrointestinal, respiratory, and neurological symptoms [20-22]. More recently, several drugs were approved by FDA for treating PD, but they also have various side effects, as summarized in Table 1 [23-27]. Hence, the search for natural products with anti-PD activity has largely increased in these years owing to their safer approach and cost-effectiveness. Though plentiful research has been carried out during the past decades on the anti-PD potential of several botanical preparations, extracts, and isolated phytocompounds, only scattered information exploring their activity is accessible. Besides, earlier reports did not provide complete information apropos plant extract doses, animals used, and their possible anti-PD mechanism.

Considering this, the present chapter attempts to provide a comprehensive report on the anti-PD potential of several botanicals in light of available experimental and clinical studies.

Fig. (1))

Genetic, environmental, and lifestyle factors leading to PD.

Table 1 Recently FDA-approved anti-PD drugs.

NEUROPROTECTIVE POTENTIAL OF BOTANICALS

Available reports reveal that functional foods, such as green legumes, condiments, cereals, different medicinal plant parts, phytoconstituents obtained from leaves, bark, fruits, flowers and seeds, crude extractives and active phytocompounds are being investigated in experimental studies, while meagre attempts are found at clinical levels. These botanicals were found to exhibit significant neuroprotective activities and have been used as potent remedies for PD. Macroscopic features of common anti-PD plants and their bioactive compounds are mentioned in Fig. (2).

Fig. (2))

Macroscopic features and bioactive compounds of medicinal plants with anti-PD potential.

In-vitro Studies

The majority of available in-vitro studies were carried out on neuronal PC-12 and SH-SY5Y cell lines, while some studies were carried out on SK-N-SH, MN9D, BV-2 microglial, D8, HT22 murine hippocampal, N9 and EOC20 microglial cell lines (Table 2). Sesamine isolated from Acanthopanax senticosus was able to decrease CAT activity, increase SOD as well as protein expression at a dose of 1 pM on PC-12 cells [28]. Protocatechuic acid isolated from kernels of Alpinia oxyphylla at a dose of 0.06-2.4 mM on PC-12 cells increases SOD, CAT, and GSH-Px levels [28], besides its ethanolic extract from ripe seeds also inhibits NO and iNOS production [29]. Aqueous and ethanol extracts from Bacopa monnieri at 50 and 10 µg/ml decreased ROS and mitochondrial superoxide levels and increased GSH levels [30, 31]. Polyphenolic catechins obtained from Camellia sinensis leaves were shown to decrease the accumulation of ROS and intracellular free Ca²+ ions, nNOS, and iNOS at a dose of 50, 100, and 200 µM [32]. EGCG, ECG isolated from Camellia sinensis exhibited anti-PD potential on PC-12 cells by activating MAPK and potentiating the ability of the cellular antioxidant defense system at a dose of 50-200 µM [33]. In PC-12 cells, EGCG also modulated DAT internalization by exerting an inhibitory effect on DAT at a dose of 1-100 µM [34]. Dried GT and BT extracts of Camellia sinensis attenuated NF-κB activation on SH-SY5Y cell and PC-12 cell at a dose of 0.6-3 µM [35].

Table 2 In vitro anti-PD activity of medicinal plants.

PD: Parkinson's disease; CAT: Catalase; DA: Dopamine, H2O2: Hydrogen peroxide; LPS: Lipopolysaccharide; NO: Nitrogen Monoxide; iNOS: inducible Nitric Oxide Synthase; ROS: Reactive Oxygen Species; MPTP: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NA: Noradrenaline; NF-κB: Nuclear factor-κB; 6- OHDA: 6-Hydroxydopamine; MPP+: 1-methyl-4-phenyl-pyridinium iodide; PI3K: Phosphoinositide 3-kinase; TH: Tyrosine hydroxylase; DAT: Dopamine transporter; MAO-B: Monoamine oxidase B; MDA: Malondialdehyde; SNpc: Substantia nigra pars compacta; SOD: Superoxide dismutase; GSH-Px: Glutathione Peroxidase; BFA: Brefeldin A; COX: Cyclooxygenase; CHOP: C/EBP Homologous Protein; PRAP: Poly (ADP-ribose) Polymerase; PI: Propidium Iodide; TG: Thapsigargin; MAPK: Mitogen Activated Protein Kinase; LDH: Lactate Dehydrogenase; LPO: Lipid Peroxidation ; CTG: Cistanche Total Glycosides; T-AOC: Total Antioxidant Capacity; GFAP: Glial Fibrillary Acidic Protein; P53: Tumor protein p53; EGCG: Epigallocatechin gallate; ECG: (−)-epicatechin-3-gallate; EGC: (−)-epigallocatechin; EC: (−)-epicatechin; GT: Green Tea; BT: Black Tea; EGb 761: Extract of Ginkgo biloba 761; PC12: Pheochromocytoma 12.

K3R and AYB, two bioactive compounds obtained from Carthamus tinctorius belonging to the Asteraceae family, at 1 μM increased cell viability on PC12 cells by Bind DJ-1 and decreased the H2O2-induced ROS levels [36]. Ripe seed ethanol extract of Cassia obtusifolia inhibited ROS overproduction, glutathione depletion, mitochondrial membrane depolarization, and caspase-3 activation in PC-12 cells at 0.1-10 µg/ml [37]. Acetosoide isolated from Cistanche deserticola at a dose of 10, 20 and 40 mg/l inhibited α-Synuclein protein aggregation in the brain [38]; tubuloside-B also obtained from its stem decreased ROS production and attenuated DNA fragmentation in PC12 cell against MPP+ induced Parkinson [39]. EGb 761, a standardized extract from Ginkgo biloba, at a dose of 10, 20, and 40 µg/ml, decreased caspase-3 activation in PC-12 cells against paraquat-induced PD [40]. Hypericum perforatum aerial part methanolic extract at 10-100 µg/ml decreased ROS level in PC-12 cells [41], as well as hyperoside isolated from the ethylacetate fraction, and at 10-180 µg/ml raised cell viability against hydrogen peroxide-induced PD [42].

Magnolol isolated from Magnolia officinalis stem bark at 30 mg/kg inhibited ROS production in SH-SY5Y cells [43]. Morus alba fruits ethanolic extract at 70% exerted antioxidant and antiapoptotic effects in SH-SY5Y cells against MPP+ induced PD at a dose of 1, 10, and 100 µg/ml [44]. Paeoniflorin, a bioactive compound isolated from Paeonia lactiflora roots, increased Hats, H3K9ac, and H3K27ac expression of Histone H3 [45]. Panax ginseng aqueous extract from rhizomes at 0.001, 0.01, 0.1 or 0.2 mg/ml decreased ROS production, Bax/Bcl-2 ratio and caspase-3 expression [46]. Ginsenoside Rg1, a bioactive compound isolated from Panax ginseng roots at a dose of 0.1-10 µM, increased cell viability by inhibiting apoptosis and oxidative stress and inhibiting NF-κB activation [47]. Resveratrol isolated from Polygonum cuspidatum rhizomes increased α-synucleins degradation in SH-SY5Y cells and PC-12 cells at a dose of 12.5, 25, and 50 µM [48]. Napthaquinone, 2-methoxy-6-acetyl-7methyljuglone is another compound isolated from P. cuspidatum that increases PC12 cell viability by inhibiting apoptotic pathways and increasing the level of antioxidant enzymes at 2.5 µM [49]. Uncaria rhynchophylla aqueous extract at 0.1, 0.5 and 1.0 µg also decreased ROS and caspase-3 activity in PC-12 cells [50].

Most aforesaid studies examined the effect of extracts, fractions, and their active compounds on SOD, GSH, CAT, DA, LDH, TH, and ROS levels; Bax/Bcl-2 ratio; caspase-3 activity; α-synuclein protein aggregation, mitochondrial activity, and NF-κB activity.

In-vivo Studies

Based on the outcomes from in-vitro reports, a few potent anti-PD botanicals were further subjected to in-vivo studies by using various neurotoxin and drug-induced anti-PD models, like 6-OHDA, rotenone, MPP+, MPTP, haloperidol, and reserpine (Table 3). Acanthopanax senticosus root and rhizome ethanolic extract at 80%, at doses of 182 and 45.5 mg/kg increased DA level in C57BL/6 mice, while 100% and 50% ethanol extract and hot water extract at 250 mg/kg also raised the DA level in Male rat of Lewis strain. Sesamin isolated from A. senticosus stem bark increased DA levels at 3 and 30 mg/kg in male rats [97]. Alpinia oxyphylla ripe seed ethanol extract at 80% decreased IL-1β, TNF-α, and NO levels and activated the PI3K-AKT pathway in zebrafish [97]. Standard extract of Bacopa monnieri at 200 mg/kg decreased NOS, MDA and HP levels in the paraquat-induced mice model; its acetone extract at 0.25, 0.50 and 1.0 µl/ml and standardized extract at 0.01, 0.025, 0.05, and 0.1% decreased NOS, MDA, HP, and oxidative stress levels and apoptosis in Drosophila melanogaster. Concentrated mother tincture of B. monnieri decreased α-synuclein aggregation and prevented dopaminergic neurodegeneration in the NL5901 strain of Caenorhabditis elegans of nematodes [98].

EGCG, a bioactive compound obtained from Camellia sinensis leaves, reduced NOS levels at 25 mg/kg and increased TH, DA, HVA, and 3,4-dihydroxyphenylacetic acid [98]. Flavonoid-rich dried flower petals extract of Carthamus tinctorius at 70 mg/kg in SD rats reduced α-synuclein aggregation and suppressed reactive astrogliosis [99-101]. Ripe seeds ethanol extract of Cassia obtusifolia at 50 mg/kg increased DA, GSH levels and decreased ROS levels in C57BL/6 mice [97]. CTG (100, 200, 400 mg/kg) and acetoside (30 mg/kg) isolated from Cistanche deserticola stem increased TH and DA levels in SD rat and C57BL/6 mice [95]. Eucommia almoidea bark at 100, 300, and 600 mg/kg increased DA, DOPAC, and HVA levels in mice [68]. Geniposide isolated from fruits of Gardenia jasminoides at 100 mg/kg in mice increased TH and decreased Bcl-2 and caspase-3 [71]. EGb 761, a bioactive compound from Ginkgo biloba leaves at 50, 100, and 150 mg/kg in rats, augmented the level of antioxidants enzymes and reduced the level of thiobarbituric acid reactive substances (TBARS) [97]. The methanol extract from Hypericum perforatum aerial part at 300 mg/kg inhibited MAO-B activity and reduced astrocytes activation in the striatal area in swiss albino mice; the standardized extract at 4 mg/kg increased antioxidant enzymes levels and decreased MDA level [97]. Fucoidan, a sulfated polysaccharide from Laminaria japonica seaweeds, augmented the level of antioxidant enzymes and decreased the level of LPO at 12.5 and 25 mg/kg in C57BL/6 mice [102]. Magnolol isolated from Magnolia officinalis bark at 30 mg/kg inhibited MAO-B and decreased the level of ROS and TBARS while increasing the AKT phosphorylation in C57BL/6 mice [43]. Morus alba fruits ethanol extract at 70%, at 500 mg/kg decreased NO, ROS and Bcl-2, and caspase-3 levels [97]. Paeoniflorin isolated from Paeonia lactiflora roots inhibited neuroinflammation by activating A1AR (adenosine A1 receptor) in mice and SD rats [97]. Ginseng extract G115 in SD rats at 100 mg/kg suppressed oxidative stress and blocked JNK signalling activation and protected dopaminergic neurons [97]. Ginsenoside Re isolated from Panax ginseng, at 6.5, 13, and 26 mg/kg in mice decreased Bax, Bax mRNA and iNOS expression and caspase-3 activation. Aqueous extract from P. ginseng at 37.5, 75 and 150 mg/kg in C57BL/6 mice led to inhibition of MAPKs and NF-κB pathways [103].

Table 3 Medicinal plants tested in-vivo for anti-PD activity.

PD: Parkinson's disease; CAT: Catalase; DA: Dopamine, H2O2: Hydrogen peroxide; LPS: Lipopolysaccharide; NO: