Indopathy for Neuroprotection: Recent Advances

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.

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.

Parkinson’s disease (PD) is a chronic, multi-system, complex neurodegenerative disorder pathologically characterized by motor dysfunctions caused mainly due to the loss of dopamine (DA) neurotransmitters producing dopaminergic (DAergic) neurons. In Ayurveda, which is an indigenous medicine system of India, various medicinal herbs have been used for the treatment of PD since ancient times. A growing number of studies have proven that these Ayurvedic herbs can protect DAergic neurons from neuronal degeneration and hence can increase the level of DA. Phytochemicals or active ingredients present in these Ayurvedic herbs can target oxidative stress, mitochondrial dysfunction, neuroinflammation, apoptosis, and autophagy and can reduce α-synuclein (α-syn) protein aggregation, which are the basic pathological causes of neurodegeneration and can improve the motor ability and sometimes longevity in animal models of PD. The mainstay of treatment of PD is levodopa (L-Dopa), a precursor of DA, used for achieving the optimal level of DA. But its long-term use has debilitating side effects. Ayurvedic herbs have provided relief in PD with no or minimal side-effect even after long-term administration. Some plants, such as M. pruriens, are a natural source of L-Dopa. Here, we have discussed the major classes of phytochemicals found in Ayurvedic medicines and the pathogenic mechanisms of PD targeted by them. After that, we have discussed the recent advances in experimental and clinical data that support the neuroprotective properties of these phytochemicals used in Ayurveda and their potential to be developed as a therapeutic intervention for the prevention of PD.

Sri Lanka is listed as the top 34th biodiversity hotspot globally and has the highest biodiversity per unit area of terrestrial in the Asian continent. Intriguingly, it has been reported that 3771 flowering plant species are grown in Sri Lanka, of which 927 (24%) are endemic to the country, and 1430 species are considered medicinal plants. Surprisingly, it is reported that up to 40% of all new molecular entities submitted to the Food and Drug Administration (FDA) approval are either natural products or natural product-derived compounds. This chapter aims to explore the therapeutic potential of Sri Lankan plants/natural products in neuroprotection as possible synergistic targets of the nuclear factor erythroid (NF-E2)-related factor 2 (Nrf2) pathway. Nonetheless, the symptoms of neurological diseases are different; oxidative stress plays a central role in pathogenesis, thus, Nrf2 activation will counteract common pathogenic processes involved in neurodegener-ative/neuromuscular disorders. Therefore, targeting Nrf2 signaling may provide a therapeutic option to delay onset, slow progression, and ameliorate symptoms of neurological disorders. However, when translating from the bench to the bedside, the knowledge of the timing of Nrf2 modulating compounds and dosage is crucial to define at which point should an Nrf2 activator be used versus an Nrf2 inhibitor. In this scenario, blends of natural products that synergize and provide multi-site action on Nrf2 regulation via different pathways are vital and will pave the way for the development of evidencebased effective neuro-nutraceuticals with a stride of innovation.

Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis are the major cause of disability and mortality. These disorders are appearing in the current era due to aging and stress-full lifestyles. For the treatments of these disorders, several conventional drugs are available but due to higher cost and dangerous adverse effects. Therefore, scientists are focusing more on medicinal herbs containing phytochemicals because these medicinal herbs are more effective, low cost, and show less harmful side effects to cure neurodegenerative disorders. Indian medicinal herbs are the most effective medicines and indigenous to India. Since ancient times, medicinal herbs have been used for treating neurodegenerative disorders. Indian medicinal herbs containing phytochemicals possess beneficial therapeutic effects for the treatment of neurodegenerative disorders, majorly having various compounds such as alkaloids, sesquiterpenes, triterpenoids, polyphenols, flavonoids, saponins, and essential oils which show anti-inflammatory and anti-oxidative properties. In this chapter, we highlighted and discussed the importance of some Indian medicinal herbs, such as Bacopa monnieri (Brahmi), Centella asiatica, Curcuma longa (turmeric), Allium sativum (garlic), Terminalia chebula (haritaki), Celastrus paniculatus (Jyotishmati), Glycyrrhiza glabra (Licorice), and Acorus calamus (Vacha) containing phytochemicals with their mechanism of action on neurodegenerative disorders.

Equilibrium in excitatory and inhibitory neurotransmitter signal transmission is necessary for the proper functioning of the brain, and alteration can stimulate the negative feedback mechanism that causes various neuropathogenesis. Disturbances like oxidative stress and alteration in the metabolism of neurotransmitters like γ- aminobutyric acid (GABA), acetylcholine (Ach), serotonin, dopamine, and glutamate, are important factors for the progression of neurodegenerative disorder (NDDs). Plant alkaloids have the potential to modulate the neurotransmitter signal transmission in the central nervous system and can provide a better alternative to the synthetic molecule. In the present chapter, we summarize the potential efficacy of plant alkaloids via functioning as anti-oxidant, monoamine oxidase (MAO) inhibitor, glutamate receptors- N-methyl-D-aspartate (NMDA) antagonist, acetylcholinesterase (AcHE) inhibitor and shows potential therapeutic effects against NDDs.

Medicinal Plants have secondary metabolites containing various phytoconstituents. Traditionally, medicinal plants are used in several diseases like cancer, diabetes, neurodegenerative disorder, etc. Flavonoids, Tannin, Phenols, Phenylpropanoids, Isoprenoids, and alkaloids are present in several medicinal plants, which play a very important role to promote health benefits and defensiveness for other disorders. Neurological disorders are prone to the elderly and difficult to treat. Several medicinal plants have been recognized as beneficial in neurological disorders. Various types of plant extract and formulations are present in ancient texts, which are effective in such disorders and should be explored scientifically to mitigate neurodegenerative disorders. In this chapter, we will focus on South Indian medicinal plants which are effective in neurological disorders or have neuroprotective properties. 

 Neurodegeneration leads to several life-threatening brain disorders such as Parkinson’s disease, Alzheimer’s disease, and many more. Such kinds of diseases have a great impact on normal life patterning and may cause other severe symptoms, which are sometimes incurable. PD is the second most common disease characterized by the symptoms like Bradykinesia, resting tremor, postural instability, and some motor symptoms involving cognitive impairment and sleep disturbance. Memory plays a major role in sustaining the life of an individual. The development of an advanced molecular technique for treating PD increases day by day, but the complications in these techniques also cannot be ignored, so scientists move towards ayurvedic herbs to treat such kinds of disorders. Bacopa monneiri is an ayurvedic medicinal creeping plant used since ancient times to treat several kinds of diseases, including brain diseases. It has many components which are useful in neuroprotection and ameliorating PD. The core aim of the present chapter is to summarize and discuss how B. monnieri plays a therapeutic role in PD

Diabetic neuropathy (DN) is a serious complication in type-1 diabetes and type-2 diabetes. Animal models show many abnormalities like neuropathy, hyperalgesia, allodynia, slow nerve conduction velocity (NCV), and progressive sensory and motor deficit that are associated with diabetic neuropathy. Various risk factors may be involved in causing DN, such as persistent hyperglycemia, microvascular insufficiency, oxidative stress, nitrosative stress, defective neurotrophism and autoimmune-mediated nerve destruction. Many conventional and newer therapeutic approaches are available. Approaches include effective control of glycemia. Symptoms targeted therapies such as antidepressants, SSRIs, anticonvulsants, opiates, NSAIDs and NMDA receptor antagonists. Therapies targeting particular causes include aldose reductase inhibitors, drugs that act on hexosamine pathways, protein kinase C pathways and AGE receptors. Preclinical studies involving pharmacological agents have shown positive results but were withdrawn at the stage of a clinical study, either due to lack of efficacy or due to their side effects on major organs. Medicinal herbal plants are the richest bio-resource of drugs that have been studied extensively for their neuroprotective effects. Various approaches involving neuroprotection by natural products are discussed here.

Autism is a complex neurobehavioral and neurodevelopment disorder with impairments in sociability, language, repetitive, and restrictive stereotypical behaviour as the core symptoms. The term “autism” was first introduced in DSM-III in the year 1980; however, it was changed to autism spectrum disorder (ASD) in DSM-V. It starts in early childhood at the age of around 3 years and persists throughout life. According to data from the Centres for Disease Control and Prevention (CDC), USA, the prevalence of ASD has increased from 1 in 88 (2008 data) to 1 in 59 (2018 data). Being a complex neurological disorder, its etiology is not clear. However, numerous neurochemical pathways have been explicated that may be responsible for the development of this disorder. Besides, it has been evidenced that immune dysfunction and genetic predisposition have a major role in its progression. Some of the major neurochemical systems implicated to be involved in its etiology are glutaminergic and GABAergic as major and others such as DAergic system, adrenergic system, serotonergic system, and the endocannabinoid system. These above-mentioned pathways are crucial in the maturation and development of neurons in different parts of the brain, thus, alteration in any of these pathways enumerates a significant role in the progression of ASD. Current treatment options are antipsychotic medications, which only provide symptomatic relief for behavioral and psychiatric complications such as irritability, anxiety, mood fluctuations,etc.. These medications are not effective in treating the core symptoms of ASD. Given the lack of effective treatment options for ASD, drugs targeting the core pathology of the disorder are the need of the hour. Although numerous studies have discussed pharmacotherapy for ASD, the present chapter, more importantly, focuses on the available treatment options for ASD and updates on the recent research approaches for the prevention and treatment of ASD.

Alzheimer's disease (AD) is a common age-related neurodegenerative disorder that results in cognitive defects. The disease is a progressive, age-associated, irreversible, neurodegenerative disease with severe memory loss, personality changes, unusual behavior and impairment in cognitive function. There is no cure for AD, and the drugs available for the treatment of the disease have limited efficacy. Medicine develops from the extract of medicinal plants have been the single most productive and common source for the development of drugs, and also, more than thousands of new products are already in clinical study. Different types of therapeutic strategies like herbal and synthetic approaches are being used against AD on the basis of understanding AD mechanisms. Ginkgo biloba extract (GBE) is the most effective and highly investigated, herbal medicine for AD and other cognitive disorders. One of the famous dietary supplements is GBE, consumed by the elderly population to improve memory and age-related loss of cognitive function. The exact mechanism of action of Ginkgo extract in AD is still not very clear. The phytochemical studies of the different plant parts of the G. biloba have revealed the presence of many valuable secondary metabolites, such as flavonoids, polyphenols, triterpenes, sterols, and alkaloids that shows a wide spectrum of pharmacological activities like anti-amyloidogenic, antiinflammatory and antioxidant effects. This book chapter gathers research on the G. biloba plant and its neuroprotective and phytochemical effects, which are used against AD. The summarized information concern pharmacological activities, neuroprotective effect, and biological and clinical applications of the Ginkgo plant.

 Neurodegenerative disease refers to the progressive deterioration of neurologic function which leads to loss of speech, vision, hearing, and movement. It is also associated with seizures, eating difficulties, and memory impairment. Natural products have emerged as potential neuroprotective agents for the treatment of neurodegenerative diseases due to the enormous adverse effects associated with pharmacological drugs. Withania somnifera (Ashwagandha) is a traditional Ayurvedic medicine, used in India as a general tonic. It contains withanolides, and phytochemicals that may have adaptogenic properties. Studies show that W. somnifera is a neuroprotective agent and can protect the brain from oxidative stress and inflammation. This explains its ability to protect from mood disorders. In this review, we have reviewed the available evidence of W. somnifera and its phytochemicals for neurodegenerative disorders. 

Aging is a process associated with distinctive changes in physiological functions and physical appearance that result from progressive tissue degeneration, harming the structure and function of vital organs. Illnesses that are particularly frequent in people 65 years of age and older are generally grouped as age-related diseases or aging-related diseases and include neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD), which are caused by progressive degeneration and/or neuronal death to produce debilitating conditions, and they have no cure. For these illnesses, the most important risk factor is aging. Aging involves changes in neuroendocrine and inflammatory responses and presents a stage with chronic and low-grade inflammation, characterized by a general increase in the production of proinflammatory cytokines, inflammatory markers, and cellular senescence. Herbal medicine, as well as various components of the human diet, including vegetables, cereals, and fruits, contain widely varied phytochemicals including flavonoids, which are the most common polyphenolic compounds. Epidemiological studies suggest that a higher intake of flavonoid-rich foods and beverages is associated with better cognitive outcomes, lower dementia rates, and reduced risk of neurodegenerative diseases. Moreover, numerous preclinical studies have shown that these compounds have a therapeutic effect on animal models of human degenerative diseases and highlight the anti-inflammatory effect of flavonoids by decreasing the activated glial cells and several proinflammatory mediators. Much modern scientific research has focused on establishing biological activities of purified single compounds to provide an evidence base for the rationale of traditional practice, and also to integrate these into modern medical practice. 

Age-related degeneration of dopaminergic (DAergic) neurons may be either genetic or due to exposure to environmental toxins that mark the onset of Parkinson’s disease (PD) pathology. Treatments like surgery and symptoms relieving drugs are available, but they have their side effects during prolonged consumption. Recent studies have shown that the use of food-derived compounds offers significant prevention and treatment of many neurological disorders. These compounds, commonly known as nutraceuticals, show immense importance in mitigating neuronal disease as there is a strong correlation between food and mental health. Accumulation of α-synuclein protein in the degenerated neurons and concomitant oxidative stressrelated pathological events are critical and known pathological markers of PD therefore, food-derived compounds containing antioxidative capacity may offer therapeutic implications. In addition, nutraceuticals are comparatively cost-effective and the safest alternatives of drugs available. Indian medicine system of Ayurveda has long been incorporating the use of herbs to cure PD. This chapter focuses on the utilization of nutraceuticals and ayurvedic preparations in PD pathology.

Mixed dementia is a form of dementia where Alzheimer's dementia coexists with vascular dementia (VaD) in the same patient. Currently, the treatment available for mixed dementia is conventional Alzheimer's dementia therapy dispensing symptomatic relief. We aim to delineate the therapeutic possibility of some secondary metabolites, which can provide manageable intervention because of their multitargeting and multiple pathophysiological components of Alzheimer's dementia and VaD. We performed the acquisition of relevant information and data by accessing and analyzing Pubmed, Science Direct, Google Scholar, and Scopus sources, to assess the validity of therapeutic use of secondary metabolites against mixed dementia. For the initial acquisition of data (in vitro, in vivo, and clinical), the keywords that were used were “secondary metabolites,” “plant extract,” “mixed dementia,” “Alzheimer's disease,” and “vascular dementia.” All types of relevant research articles, review articles, and books were included. In our study, clinically, preclinical, in vivo, and in vitro studies of secondary metabolites are encompassed. Furthermore, we undertook the formulation of the mechanism of action of secondary metabolites in terms of systems biology-oriented analysis and signal transduction-based methodology. Firstly, the likely mechanisms through which mixed dementia can take place are identified and analyzed rigorously. Secondly, we demarcate the pharmacological actions of the secondary metabolites in treating mixed dementia by (i) Targeting acetylcholine levels, (ii) Reducing or dissociating amyloid-beta (Aβ) load, (iii) Modulating microglial activation, and (iii) Providing vasodilation concurrently with their various constituents of Alzheimer's dementia and VaD. Thirdly, we formulate how several preclinical and clinical studies furnish evidence that secondary metabolites may have efficacy in Alzheimer's patients with cerebrovascular disorders.

We formulate comprehensive evidence to substantiate the use of secondary metabolites from medicinal plants to enhance therapeutic intervention in mixed dementia.