Title: Neuroprotective Role of L-N.sup.G-Nitroarginine Methyl Ester (L-NAME) against Chronic Hypobaric Hypoxia with Crowding Stress (CHC) Induced Depression-Like Behaviour
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Author(s): Satya Narayan Deep 1 , Iswar Baitharu 2 , Apurva Sharma 3 , Anoop Kishor Singh Gurjar 4 , Dipti Prasad 1 *, Shashi Bala Singh 1

Introduction

Exposure to stress causes multitude of neurochemical, neurotransmitter and hormonal alterations in brain to evoke appropriate responses suitable for adaptation. Studies on chronic physical, psychological or mixed stress model have been reported to invoke proinflammatory responses characterized by a complex release of several inflammatory mediators in the brain and other systems [1]. Under physiological conditions, these proinflammatory cytokines enhance neurogenesis. However, excessive or prolonged cytokine exposure may damage the brain by affecting the metabolism of neurotransmitter and neuropeptide, neuroendocrine and neural plasticity, decreasing neurogenesis, increasing glutamatergic activation, oxidative stress and induction of apoptosis [2,3,4]. Chronic stress mediated elevation in proinflammatory cytokines, oxidative and nitrosative stress markers in several brain regions have been designated as a major cause of neurodegeneration and consequent pathological manifestation of depressive disorder [5,6,7,8,9]. Further, several reports show a close association of enhanced neuroinflammation with many neurological diseases and disorders showing co-morbid depressive symptoms [10,11,12]. Drugs interfering with the detrimental consequences of stress on inflammatory pathways offer novel treatments for mood disorders and subsequent neurodegenerative pathologies. However, the mechanism underlying stress induced microglial activation and its relationship with the symptomatic manifestation of depressive illness is poorly investigated.

Nitric oxide (NO), a free gaseous signaling molecule and a retrograde neurotransmitter, is widely reported to be involved in the regulation of the nervous and immune system. Several studies suggest the involvement of neuronal nitric oxide producing enzymes nNOS in the pathophysiological mechanism of depression-like behaviour in rodents [13,14]. NOS-positive neurons are located in the hippocampus, cerebral cortex and other encephalic regions [15]. Regulation of nitric oxide level in the brain using NOS inhibitors attenuates the depressive effect of chronic stress [16,17,18]. Peng et al. (2012) showed that stress-related depressive-like behaviour could be abrogated remarkably by pre-treating the mice with an iNOS inhibitor [19]. Though both elevated nitric oxide and neuroinflammation occur in various depressive disorders, there are very few studies demonstrating the association of nitric oxide with microglial activation in stress induced depression.

Microglia are the major glial component of the central nervous system (CNS) that mediate neuroinflammation through the release of pro-inflammatory cytokines and nitric oxide (NO). Microglia plays a critical role as resident immunocompetent and phagocytic cells in the CNS. Under physiological condition, microglia remains in resting stage with numerous branching in adult brain and continuously surveying its vicinity to phagocytose the harmful agents. They also play a very important role in shaping adult neurogenesis by apoptosis coupled phagocytosis of newly born neurons. But when they are challenged due to stress or inflammatory agent, they become motile and their morphology change and become active. Active microglia secrets proinflammatory cytokines and other reactive stress mediators like reactive nitric oxides. Active microglia are hypertrophic or ameboid-like which initiate an inflammatory response through the secretion of proinflammatory cytokines [20] and phagocytose dying cells [21]. However, the mechanism underlying the microglia activation in depression and its role...

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Source Citation (MLA 8 th Edition)
Deep, Satya Narayan, et al. "Neuroprotective Role of L-N.sup.G-Nitroarginine Methyl Ester (L-NAME) against Chronic Hypobaric Hypoxia with Crowding Stress (CHC) Induced Depression-Like Behaviour." PLoS ONE, vol. 11, no. 4, 2016. Academic OneFile, Accessed 22 May 2019.

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