Traditional Medicine for Neuronal Health

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.

Neurodegenerative disorders are threatening mankind with significant health and economic burden. Neurodegeneration involves the deterioration of neurons in the central nervous system (CNS), resulting in decreased neuronal survival. Therefore, it is of utmost requirement to develop a promising pharmacological strategy to minimize or prevent the progression of the underlying disease pathogenesis. In neurodegenerative disease conditions, neurons and glial cells present in the specific brain regions are damaged and depraved, resulting in specified disease symptoms in the patients. Neuroinflammation plays a major role in the degeneration of neuronal cells by regulating the expression of interleukin-1 beta (IL-1β), IL-6, IL-8, IL-33, tumor necrosis factor-alpha (TNF-α), chemokines Cxcl3 (C-C motif) ligand 2 (CCL2), CXCL5, granulocyte-macrophage colony-stimulating factor (GM-CSF), glia maturation factor (GMF), substance P, reactive oxygen species (ROS), reactive nitrogen species (RNS), impaired tuning of immune cells and nuclear factor kappa-B (NF-κB). Considering this, it is very important to understand the in-depth role of neuroinflammation in the initiation and progression of various neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), as well as Multiple Sclerosis (MS). Recent shreds of evidence have suggested that using exogenous ligands to approach various biological molecules or cellular functioning that modulates the neuroinflammation, such as microglia response, P2X7 receptors, TLR receptors, oxidative stress, PPARγ, NF-κB signaling pathway, NLRP3 inflammasome, caspase-1 signaling pathway, and mitochondrial dysfunction, helps to combat neurodegeneration in a variety of diseases. Thus, targeting the neuroinflammatory drive could provide a beacon for the management of neurodegenerative diseases. Here, we have attempted to provide comprehensive literature suggesting the role of neuroinflammation in neurodegeneration and its implication in the development of near-future neurotherapeutics.

Neurodegenerative disorders are the conditions in which neurons of the central and peripheral nervous systems degenerate. Various cellular and molecular processes are associated with the progression of such degeneration, including inflammation, apoptosis, and axonal degeneration. Recently, SIRTUINs have emerged as one of the key factors associated with neurodegenerative disorders. SIRTUINs are involved in the regulation of several cellular and molecular processes in neurons of the nervous system through the deacetylation of target proteins. The chapter focuses on the modulatory role of SIRTUINs in neurodegenerative disorders and their potential therapeutic application. 

Fungal endophytes are a group of fungi that reside in plant tissues and show a symbiotic relationship with the host plants. They protect against pathogens and increase food availability without causing any harmful effects on the host plant. Fungal endophytes are known to produce a wide range of bioactive compounds with several biological activities, including neuroprotective effects. Neurodegenerative disorders lead to miscommunication between nerve cells, damage or loss in structure and function of the central nervous system (CNS) or peripheral nervous system (PNS). Reactive oxygen species, neuroinflammation, protein degradation or aggregation, familial history, mutation in mitochondrial genes, and aging contribute to neurodegenerative disorders. Plant-associated fungal endophytes produce bioactive compounds, which show anti-neuroinflammatory, antioxidant, and anti-cholinesterase activities. Several pro-inflammatory (TNF-α and NF-κB) and depressant (serotonin, dopamine, and noradrenaline) molecules or neuronal signaling pathways leading to neurodegenerative disorders are known to be inhibited or down-regulated by fungal endophyte-derived bioactive compounds. Therefore, bioactive compounds produced from fungal endophytes could be a promising approach to treating various health ailments. The present chapter discusses selected fungal endophyte-derived potential bioactive compounds with neuroprotective effects for managing neurodegenerative disorders.

The term neurodegenerative disease means the loss of neuronal cells in the brain, including Alzheimer's disease, Parkinson's disease, Multiple sclerosis, and Huntington's disease. It is one of the most common types of disease associated with elevated rates of mortality and morbidity worldwide. At the same time, modern allopathic medicines have a large number of synthetic chemicals for the symptomatic treatment and control of these diseases. These drugs have failed miserably due to clinical insufficiency and debilitating adverse effects. In the past decade, natural ingredients have gained notable interest in the prevention and treatment of neurodegeneration due to their powerful anti-inflammatory and anti-oxidant properties with minimal side effects. However, there is also an issue of safety and effectiveness due to the absence of an ample amount of research findings. The most common cellular mechanism for every neurodegenerative disorder is neuroinflammation and oxidative stress. Several preclinical and clinical studies conducted across the world have demonstrated that different bioactive compounds of herbal origin can potentially arrest these processes to prevent or treat neurodegeneration and can be developed into promising pharmaceutical formulations. This article discusses and analyses the various herbal compounds, such as Allium sativum, Camella sinensis, Centella asiatica, Coriandrum sativum, Crocus sativus, Glycyrrhiza glabra, and Morus alba used for phytotherapy of neurodegenerative diseases by combining recent in vitro and in vivo models.

Tinospora cordifolia is a Rasayana herb of Ayurveda, commonly known as “Heavenly Elixir” or “Amrita”, and one of the most exploited herbs in herbal medicines. T. cordifolia is well reported for its various pharmacological properties, such as anti-diabetic, anti-inflammatory, antipyretic, immunomodulatory, anti-cancer, cardioprotective, neuroprotective, and hepatoprotective activities. The prevalence of neurodegenerative diseases and other neurologic disorders is increasing worldwide. Oxidative stress and neuroinflammation are among the major pathologic mechanisms underlying neurodegenerative diseases. This chapter discusses the pieces of scientific evidence of the beneficial effects of T. cordifolia in various brain-related ailments. Various research groups have demonstrated the ability of T. cordifolia and its extracts to normalize oxidative stress and suppress the inflammatory response against various causative agents, and thus suggested that T. cordifolia has the potential to be a neurotherapeutic drug candidate in the future.

Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease affecting the aged population. The variable loss of dopaminergic neurons within substantia nigra pars compacta (SNpc) of the brain, which controls movement, and the presence of intracellular protein aggregates called Lewy bodies are major pathological findings. The recent years’ research in PD is directed to herbal drug discovery for PD as a large number of patients, particularly in western countries, prefer to use “natural therapies” and drugs instead of pharmaceuticals. Kapikachhu (Mucuna pruriens Linn.) is one of the popular drugs in Ayurveda, the classical system of medicine in India. The seeds of M. pruriens contain 5% L-3, 4-dihydroxyphenylalanine (L-DOPA), and it has emerged as a promising single drug treatment of PD. The present manuscript is an attempt at obtaining complete knowledge regarding Parkinson’s disease as mentioned in Ayurveda for achieving a natural and holistic approach to better management and prevention of disease with herbal drugs, such as M. pruriens. 

The disorders of the central nervous system are increasingly recognized as one of the most prevalent disorders in the present world. It has been envisaged that neurological disorders will be of great concern in the present and future populations worldwide. The different neurological disorders may be associated with signs, such as loss of memory, impaired brain function, cognitive deficits, etc. The occurrence of such degenerative diseases of the nervous system certainly imposes medical and public health burdens on populations worldwide. The multifactorial nature of such neural disorders entails the use of modern medicine in combination with conventional medicines for treatment. There has been undeniably a revolution in the foundation of existing medical facilities, which have been strengthened by the amalgamation of phytomedicine. In recent times, the use of medicinal herbs to improve mental function has come into the limelight in both developed and developing countries. Increased research is being carried out to discover Ayurvedic medications owing to their biosafety profile and utility in cognitive impairment. The current chapter deals with the depiction of one such plant, that is Bacopa monnieri, which possesses neuroprotective properties, and is considered to be Medhya Rasayana (a nootropic drug). This Indian herb, being a dietary anti-oxidant, has several modes of action to protect the brain against oxidative damage and age-related issues. A majority of the plant compounds, such as polyphenols, alkaloids, and terpenes, present in medicinal plants, have been known to have therapeutic properties against neurodegeneration mainly by virtue of their antioxidant, anti-inflammatory, and anti-amyloidogenic effects. 

The global burden of neurological diseases is increasing at a much faster rate causing a social and economic impact on the people. Neurological diseases, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, and many more, are the current hot topics. The current treatment strategy in combating neurological diseases only focuses on symptomatic relief and thus causes severe side effects. Therefore, the therapeutic approach to combating neurological diseases has shifted towards herbal plants. One such plant of great importance is Curcuma longa L. and its associated active constituent curcumin. In this book chapter, we have focused on the important role of curcumin in neurological diseases, in which we have summarized data from 10 years (2010-2020) to get a comprehensive idea for further research in this field. We have also described the role of curcumin in the treatment of neurological diseases, including its cellular and common molecular mechanisms.

Anxiety and depression are the major psychological disorders globally, increasing the risk of morbidity and mortality and considerably leading to a socioeconomic burden by 2030. Both disorders impact day-to-day life via several symptoms (fear, insomnia, anorexia, irritability, loss of concentration, and inability to think). The available treatment strategy for psychological disorders has shown major adverse effects, which limits its use and paves the way for the development of the herbal drug-based novel drug. Natural compounds are offered as the most contented option because they possess very least side effects, are easily available, and are of low cost with high therapeutic activity. In the present chapter, we focus on the pharmacology of a plant polyphenol, Rosmarinic acid (RA), against psychological disorders. Specific plant constituents of Rosmarinus officinalis (rosmarinic acid) help treat anxiety and depression by reducing oxidative stress and inflammatory mediators. Other important targets, such as neurotransmitters (noradrenaline, 5-HT, and dopamine), neuroendocrine (Hypothalamus-pituitary-adrenal-axis), brain-derived neurotrophic factor, T-type calcium channels, mitogen kinase protein-1, and phosphorylated extracellular regulated kinase 1 and 2 protein, are also involved in the pathophysiology of psychological disorders (anxiety and depression). Thus, in this chapter, we have illustrated the pharmacology of RA in major psychological disorders, including anxiety and depression. 

Berberine is an isoquinoline alkaloid obtained naturally from the roots, rhizomes, and bark of various plant species, such as Berberis, Phellodendron, etc. It is an integral part of various medical systems, such as Ayurveda, Chinese traditional medicine, and Yunani medicine. It possesses various properties, such as anti-diabetic and anti-obesity properties, controls lipid profile, and is a strong antioxidant that helps in protecting against oxidative stress. It acts on multiple pathways throughout the brain and periphery to exert a wide variety of effects that can be beneficial for human use. Berberine is effective in protecting against neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and ischemia, and it also protects against neuropsychiatric disorders, such as schizophrenia, mania, anxiety, and depression. It is a potent PI3K/Akt pathway activator, decreases proinflammatory cytokine production, reduces glutamate excitotoxicity, triggers the synthesis of neurotrophic factors, increases levels of biogenic monoamines, such as serotonin, dopamine, and norepinephrine, and shows anxiolytic effects by modulating GABA levels. In this chapter, we discuss how berberine mediates these effects, modulates which pathways in the brain and body, and how does it provide a wide array of responses.

Resveratrol is a naturally occurring polyphenol (stilbenoid) that works as a phytoalexin, a part of plants’ defense system against infection, ultraviolet radiation, stress and injury. Common dietary sources of resveratrol include grapes, berries, peanuts, red wine, and some herbal preparations. In animal models, resveratrol exhibits a wide spectrum of potential therapeutic activities, including antioxidant, antiinflammatory, neuroprotective, and longevity-promoting properties. Resveratrol mimics the antioxidant, anti-aging, and neuroprotective effects of caloric restriction, mainly mediated through the increased expression of genes encoding antioxidants and the anti-aging factors (AMPK and Sirtuin 1). Therapeutic strategies for the treatment of neurodegenerative diseases currently have several shortcomings. Naturally occurring compounds may play a significant role in augmenting these therapeutic options. Resveratrol has been shown to maintain homeostasis, protect the brain against oxidative stress, preserve neuronal function, and ultimately minimize age-related neurological decline. It has shown positive effects in animal models and cell culturebased experiments in treating Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, Huntington’s disease, and other neurodegenerative diseases. Resveratrol enhances learning memory and neurogenesis and alleviates neural apoptosis in the hippocampus of AD mice. Beneficial effects of resveratrol in PD result from the inhibition of α-synuclein aggregation and cytotoxicity, lowering of total and oligomeric α-synuclein levels, reduction of neuroinflammation, and oxidative stress. Clinical trials are also evaluating the role of the drug in the major neurodegenerative disorders.

Diabetes is a hyperglycemic metabolic condition. Diabetes may lead to obesity and neuropathic changes in a patient. Damage to any neurological part or organ during diabetes causes diabetic neuropathy. Neuropathy occurs due to hypersensitivity in nerves because of abnormal epinephrine-mediated transmission of the impulse from axon to axon. In 1864, Marchal de Calvi explained that diabetes causes neurologic lesions by observing the pain in sciatic distribution and peripheral areas of anesthesia. Anti-hyperglycemic components, polypeptide-p and osmotin, can not only reduce the blood glucose level of mice but have also proven to be without any side effect or negative impact as they reduce oxidative stress level, improve the activities of endogenous antioxidants, and positively alter the activities of neurotransmitters, like cholinesterase, serotonin, and γ- aminobutyric acid (GABA).

Alzheimer's Disease (AD) is an irreversible and progressive neurodegenerative disorder that directly deteriorates the memory and cognitive function of the human brain in such a way that a person finds difficulties in dealing with daily life tasks. It is characterized by irregular neurofibrillary tangles (NFTs), intraneuronal accumulation, and the development of senile plaque (SP) consisting of abnormal polypeptide accumulation called βA4 amyloid. The pathophysiology can be collectively explained by five major hypotheses that are amyloid β (A β) hypothesis, the hyperphosporelated tau hypothesis, chronic inflammation, the cholinergic hypothesis, and the metal ion hypothesis. WHO estimated that a total of 40 million people worldwide are tested for the ill effects of dementia, and this is predicted to be twice as high as 114 million by around 2050. Currently, FDA-approved treatments for Alzheimer’s involve Donepezil, Rivastigmine, Galantamine, and Memantine that do not act specifically against Alzheimer's pathology and are also associated with loss of appetite, increased frequency of bowel movements, mental confusion, and dizziness as their side effects promote the approach to disease-modifying drugs. Nowadays, treatment with herbal medicines is a powerful alternative worldwide due to their high safety of margin against the side effects of allopathic drugs. Herbs are not restricted to a specific activity; they are generally enclosed with lignans, flavonoids, tannins, triterpenes, sterols, and alkaloids with wide pharmacological activities, such as antiinflammatory, anti-amyloidogenic, anti-cholinesterase, and anti-oxidant effects. Many herbal plants of India, such as Glycyrrhiza glabra, Acorus calamus, Convolvulus pluricaulis, Centella asiatica, Sesbania grandiflora, etc., have already proved their efficacies in treating dementia in various scientific studies.

Age-associated neurodegenerative disorders are a growing cause of mortality and morbidity in the elderly population globally. The patients suffering from neurodegenerative disorders pose medical, economic, and social issues. The agingassociated neurodegenerative disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), have different clinical and neuropathological signatures, but they share a pattern of neurodegeneration in anatomical and functionally related regions. Natural products offer great potential in the prevention and therapy of neurodegenerative diseases. Plant-derived products protect neurons by targeting oxidative stress, mitochondrial dysfunction, neurotrophic factor deficit, and abnormal protein accumulation. The current chapter discusses the neuroprotective effect of natural products in the prevention of aging-associated neurodegenerative disorders.