Immunomodulatory Effect of Plant-Based Extracts on Neurodegeneration

KOEL SINHA and CHITRANGADA DAS MUKHOPADHYAY

Center for Healthcare Science and Technology, Indian Institute of Engineering Science and Technology, P.O., Botanical Garden, Shibpur, Howrah, West Bengal - 711103, India, E-mails: This email address is being protected from spam bots, you need Javascript enabled to view it (K. Sinha), This email address is being protected from spam bots, you need Javascript enabled to view it (C. D. Mukhopadhyay)

ABSTRACT

Mechanisms including blood-brain barrier (BBB) integrity, oxidative stress, chronic stress, hippocampal neurogenesis, microglial activation and chronic low-grade neuroinflammation, have shown to be related to cognitive changes across age. Supplementation with one or more plant based extracts or nutra- ceuticals that act on these mechanisms may be an important next step toward preventing age associated cognitive decline. Dopamine (DA) and serotonin (5-HT) are the main neurotransmitters found in the central nervous system (CNS) which possess immunomodulatory functions. Various experimental evidences support that these molecules are involved in modified cytokine secretion, apoptosis and cytotoxicity. Extracts from Withania sonmifera, Bacopa monnieri, Gingko biloba, and Curcuma longa are being studied for their anti-inflammatory and immunomodulatory properties as well as their cognitive enhancing effects. Extraction is considered to be the important step in the analysis of constituents and the following mentioned extraction techniques such as soxlilet, room temperature, super critical fluid extraction are used. A neurotransmitter profiling findings are useful in pharmacological regulation of the serotonergic and dopaminergic system modulated immune function and may help in establishing therapeutic alterations. The translational gap between in vitro, in vivo and clinical studies is still a major issue especially with respect to immunomodulatory effects. So this study aims to join that gap in a holistic approach.

INTRODUCTION

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) are generally characterized by progressive loss as well as the death of neurons [1]. One of the main causes of neurodegenerative disease is aging, which carries mitochondrial dysfunction, chronic immune-inflammatory response, loss of blood-brain barrier (BBB) integrity, enhancement of oxidative stress, and reduction of hippocampal neurogenesis along with anchorage of chronic low-grade neuroinflam- mation [2]. Besides, neuronal loss interplay between adaptive and innate immune system also performs an important role in the onset and progression of neurodegenerative diseases. Interestingly, immune in an organism acts as a major defense mechanism for protection against foreign invaders as well as to eliminate diseases. They include the involvement of many types of cells of which some function either as immunostimulants or as immunosuppressors [3]. The process of enhancement of immune reactions is termed as “immunomodulation” which mainly involves the stimulation of non-specific systems. Thus, the suppression of the immune system’s elements may allow the pathogenic organisms to surge over the host and may lead to secondary infections [4].

The knowledge about the neurodegenerative disease etiology and immunomodulatory outcomes targeted therapies like neurotransmitter modulators, stem cell-based therapies, hormone replacement therapy, neurotrophic factors, as well as regulators of the mRNA synthesis and its translation into disease-causing mutant proteins have been developed [5-10]. Therefore, the above strategies are great tools to combat neurodegeneration and are often associated with adverse effects and long-term unknown consequences [7, 11]. Neural transplantation and stem cell-based therapies are emerging trends to fight against the neurodegenerative diseases. Despite the advancement in these fields of research, the therapeutic applications of such novel tools are still far from reaching the clinics. Therefore, there is an immense urge towards a long duration alternative therapeutics to combat against this debilitation neurodegenerative disease. Currently, a new approach towards immunomodulation with medicinal plants has been developed for enhancing the host defense mechanism against neurodegenerative diseases. In the Indian medicinal system, a huge number of plants along with their bioactive constituents exhibit immunomodulatory characteristics and hence can be considered as a safer alternative to reduce the adverse effects of modern drugs in the immunological system. Besides, whole plants as well as secondary metabolites can also be used as drugs to treat several neurodegenerative diseases. Not only phytodrugs, but rasayana drugs also plays a crucial role towards the improvement of defense mechanism as well as immunomodulatory activity. Also, many nutraceuticals like proteins, alkaloids, phenolic compounds show immunomodulatory characteristics along with anti-oxidant and anti-inflammatory properties. In this chapter, we will provide a review on some of the plant-based extracts with established immunomodulatory properties and their efficacy in treating neurodegenerative diseases has been discussed along with a broader vision and a better understanding of how these diseases could be related to each other along with the immunomodulatory property of neurotransmitter on various neurodegenerative diseases.

NEURODEGENERATIVE DISEASES

Neurodegenerative diseases are incurable and debilitating conditions leading to chronic brain damage and neurodegeneration. The etiology of the disease is still elusive, although improved experimental models showed miserable conditions associated with mutated genes, accumulation of abnormal proteins, increased reactive oxygen species (ROS), or destruction of the neurons in a definite area of brain.

2.2.1 ANATOMY AND FUNCTION OF NEURODEGENERATIVE BRAIN

Besides, the classical symptoms, neurodegenerative disease also show other signs and symptoms such as weight loss, abnormal mood, and endocrine perturbations Moreover, major damage is caused in the small brain structure in the ventral side of brain known as hypothalamus symmetrically located on both the sides of the third ventricle. The hypothalamus carries signals from the CNS to the periphery and regulates several functions including reproduction, intake of food, and control of circadian rhythm as well as sleep-wake cycle. Indeed, alteration in normal condition of hypothalamus has been observed in pre-symptomatic carriers or in patients with initial phase of neurodegenerative disease [12]. Furthermore, pathological aggregates and multiple neuropeptidergic populations in the hypothalamus of most neurodegenerative disease patients leading to the observed metabolic phenotype as well as to other non-metabolic symptoms. Despite pathological evidence, to date, a few studies have determined the functional role of hypothalamic alterations in the case of both neurodegenerative disease progression and dysfunction.

  • 2.2.2 MECHANISMS ASSOCIATED WITH NEURODEGENERATION
  • 1. Mitochondrial-Mediated Neurodegeneration: Manifestations of neurodegenerative diseases such as AD, PD, HD, MS, and ALS are largely associated with mitochondrial damage [13-16]. Several mitochondrial-dependent mechanisms such as inhibition of mitochondrial electron transport chain (ETC)’s complexes, ROS generation, and impairment of mitochondrial dynamics could contribute to the pathogenesis of neuronal injury as well as neurodegenerative diseases [17, 18]. Mitochondrial abnormalities and defective ETC (Complex I) present in substantia nigra is the foremost cause of neuronal damage in AD, PD, and ALS whereas, neuronal damage in MS is also attributed to Complex I and IV of the ETC along with the loss of mitochondrial membrane potential (A47J [19, 20]. Furthermore, evidences from clinical studies suggested the active role of mitotoxicity in the neuronal degeneration in HD [13]. Huntingtin, the gene responsible for HD, is reported to directly impair the mitochondrial functions [21]. Based on these findings it can be concluded that mitochondrial damage is the primary event observed in various neurodegenerative diseases. Owing to complex interplay between mitochondrial-toxicity and oxidative stress, it has been unclear whether mitochondrial damage is the main consequence of neuronal damage. Evidences also proved that mitotoxicity-related oxidative stress is also the leading cause for the development of neurodegeneration.
  • 2. Oxidative Stress-Mediated Neurodegeneratiou: Our nervous system is vulnerable to oxidative stress due to several reasons including: (i) high oxygen consumption, (ii) relatively lower level of endogenous antioxidants, (iii) polyunsaturated lipids susceptible to free radical in the plasma membrane of large neuronal cells, and (iv) presence of excitatory neurotransmitters whose metabolism can produce ROS [22-24]. These characteristics make neuronal cells highly prone to ROS-mediated damage. Neuronal degeneration in

AD patients is associated with the oxidative damage to DNA, RNA, proteins, and lipids whereas; oxidative damage to DNA and protein has also been reported in the nigro-striatal region in PD [25-27]. Moreover, oxidative stress-mediated mutations in the gene coding for the ubiquitous Cu/Zn-superoxide dismutase (SOD-1) enzyme and damage to the biomolecules have been associated with the familial forms of the ALS [28, 29]. On the other hand, ROS produced by the activated microglia and mononuclear cells and performs a crucial role in MS pathogenesis. Indeed, oxidative damage to nuclear DNA, mitochondrial DNA has been linked to demyelination and axonal injury in MS [30]. Therefore, all these evidences clearly indicate a causal relationship between the oxidative stress and neuronal degradation.

2.2.3 SYMPTOMS OF NEURODEGENERATION

Although, our understanding about the symptoms involved in neuronal damage has increased in recent years, due to advanced medical technology. The symptoms generally vary from agitation, irritability, and impulsivity followed by apathy and indifference. Other symptoms vary from depression to euphoria, from delusions and hallucinations to anxiety and sleep disturbance, from loss of empathy and socially inappropriate behavior along with changes in eating behavior and stereotyped behaviors such as pacing, wandering, and rummaging. These changes cut across diseases and occur frequently in AD, PD, and a host of other conditions including HD and corticobasal syndrome (CBS) [31].

2.2.4 TREATMENTS AND DRAWBACKS OF NEURODEGENERATIVE DISEASES

Till date, it has been impossible to find a proper cure against neurodegenera- tive diseases, but medication and therapeutic strategies available nowadays has been addressed to improve the quality of life in patients. Although, there are some treatment options which are effective in enhancing the treatment of AD and PD to some extent. But still now no feasible treatment options have been discovered against ALS and HD. Regarding PD, the association between carbidopa and levodopa represents a potential standard for symptomatic treatment of PD [32]. Levodopa is a natural chemical in brain, when combined with carbidopa can be easily converted to dopamine

  • (DA). This carbidopa generally prevents conversion of levodopa to DA before entering the brain. Indeed, this is most effective treatment against PD, but due to long-term use, the effect starts to fluctuate. Other various side effects experienced includes nausea, feeling of light-headedness, and sudden involuntary movements. Moreover, the association between levodopa and catechol-O-methyltransferase inhibitors helps to prolong the effects of levodopa by blocking brain enzymes that deplete DA concentration. These side-effects are similar with that of levodopa mainly diarrhea and involuntary movements. With regard to dopaminergic, agonist which generally mimics the DA effect in the brain and are generally not effective as levodopa but the effects are long lasting and can be used in conjunction with levodopa to counter any fluctuation in efficiency. These types of medications can be administered by oral medications or as an injection. The side effects are drowsiness, hallucinations, and compulsive behaviors such as gambling and overeating. This intervention needs careful evaluation due to its adverse side effects and requires a gradual interruption of the therapy. Though already proved effective in amelioration of symptoms but most of the above treatment strategy are unable to undergo modification in terms of disease evolution and progression. Therefore, it is necessary to develop fruitful therapies that provide neuroprotective effects and slows down the progression of neurodegeneration mechanisms involved in PD. With regards to the treatment options for AD, it has no significant effect either on symptoms or disease progression. The current approved treatments against AD utilizes two strategies such as symptomatic and disease-modifying treatment. In this scenario, for symptomatic treatment anticholinesterase inhibitors act as a potent component. On the other hand, for disease-modifying treatment antioxidant and anti-inflammatory agents could be used. Moreover, recent treatments for AD patients temporarily became successful in slowing cognitive deteoriation in AD. The effects of these strategies are at its best marginal and are prescribed as there is not anything better option to be used to fight against AD. Various ongoing clinical trials and the search for effective drug against AD being pursued worldwide based on its pathogenetic mechanisms.
  • 2.2.5 TREATMENT OF NEURODEGENERATIVE DISEASE WITH PLANT EXTRACTS

As the current therapies are symptomatic not curative led to the discovery of new drugs for effective treatment of neurodegenerative diseases.

Furthermore, the treatment for chronic neurodegenerative diseases require long-term drug administration with effective targeted drug delivery system along with reduced side-effects. Based on the above considerations, the plant-based extract could be an interesting candidate as therapeutic agent because of its anti-oxidant and anti-inflammatory properties. In the last two decades, there has been a massive interest for the usage of plant extracts and its metabolites as drug and this is because of the rapid advancement of various teclmiques such as NMR, HPLC-MS/MS, high-resolution Fourier transform mass spectrometry (MS) and so on [33]. Although, few plant extracts proved to be beneficial due to their in-vivo disease protecting features and also turned out to be non-essential nutrients for human beings. Some of these extracts are efficient in regulation of several cellular as well as molecular pathways due to these innumerable properties they are evidenced to play a beneficial role for human health [34]. Hence, the in-vitro and in-vivo effects of plant extracts have shown intense role in disease prevention along with their ability towards treatment and prevention of neurodegeneration. The association between L-dopa and carbidopa, a peripheral inhibitor of enzyme DOPA decarboxylase represents the gold standard for the symptomatic treatment of PD [13]. Carbidopa is involved in the inhibition of the conversion of L-dopa to DA peripherally, thus, it guarantees that a higher level of the drug reaches the central nervous system (CNS). Currently, L-dopa represents the most effective impossible to assume single patient’s response to this drug, some motor symptoms, namely bradykinesia, rigidity, and postural instability, ameliorate 70% from the first weeks of the treatment [18].

 
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