Relationship between Central Cholinergic System and Neuroinflammation: A Molecular Pharmacological Approach
IR@CDRI: CSIR-Central Drug Research Institute, Lucknow
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Tyagi, Ethika
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| Date |
2014-09-10T05:54:08Z
2014-09-10T05:54:08Z 2009 |
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http://hdl.handle.net/123456789/1397
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Guide- Dr. Rakesh Shukla, Phd Thesis Submitted to Chhatrapati Sahu Ji Maharaj University, Kanpur in 2009.
Inflammation is a local, protective response to microbial invasion or injury. It must be fine-tuned and regulated precisely because inflammatory damage may cause morbidity and shorten lifespan. Acute brain injuries such as ischemia and trauma have in common some pathophysiological mechanisms similar to inflammation leading to brain tissue destruction and functional impairment. Neuroinflammation is one of those, affecting the outcome of brain injuries. It is a process that results primarily from the presence of chronically activated glial cells (astrocytes and microglia) in the brain, and is a characteristic feature of both acute and chronic CNS disorders (Akiyama et al., 2000). Controlling neuroinflammation has been considered a promising approach to treat neurodegenerative disorders such as Alzheimer’s disease (AD). The contribution of the inflammatory component to disease progression has led to novel attempts aimed at discovering ways to attenuate inflammation therapeutically (Nathan, 2002). The equilibrium between the secretion levels of pro- and anti-inflammatory cytokines and their sequential release may be one of the key determinant factors that accounts for the severity of the inflammatory responses. Any alteration in this equilibrium may convert a beneficial inflammatory response into a severe pathological inflammatory outcome. Consequently, great attention is currently devoted to cellular mechanisms which control cytokine levels in neuroinflammatory conditions. Lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, stimulates the immune system through activation of macrophages in peripheral tissues. LPS also activates glial cells in brain releasing inflammatory cytokines such as tumor necrosis factor- α (TNF-α) and interleukin-1β (IL-1 β). In response to these cytokines, several reactive oxygen species (ROS) are produced, establishing a status of oxidative stress (Sugino et al., 1987). Activation of microglia has also been observed during the development of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases (McGeer et al., 1998). Pro-inflammatory mediators released by activated glial cells during brain inflammation have been proposed to contribute to neuropathology underlying cognitive deficits in Alzheimer's disease (AD) (Oken, 1995). A role for neuroinflammatory processes in Alzheimer’s pathogenesis has received further support from epidemiologic studies showing a protective effect of anti-inflammatory medication (Rich et al., 1995). During neuroinflammatory conditions, activated glial cells are known to release nitric oxide (NO) and prostanoids which are likely to have a crucial role in mediating the interactions between glial and other cells present in brain, as they are known to regulate inflammation, immune functions, blood vessel dilatation, neurotransmission, and neural cell survival (Minghetti et al., 1997). Microglia appears to be the main and earliest reactive cells; they are considered as the sensor for pathological events within the brain. Secretary products of activated glial cells have been shown to selectively disrupt neurochemical systems — acetylcholine (Araujo et al., 1989) and cellular functions in hippocampal (Hausswegrzyniak et al., 1998) and basal forebrain (McMillan et al., 1995), which are involved in learning and memory processes. Among the endogenous mechanisms, cross-talk between the immune and nervous systems plays an important role to regulate the inflammatory responses. Cholinergic system has been suggested as mediator of neuro-immune interactions, or internal regulator of immune responses (Nizri et al., 2006). Immune cells possess a complete cholinergic system consisting of acetylcholine (ACh) muscarinic and nicotinic receptors (mAChR and nAChR), choline acetyl-transferase (ChAT) and acetylcholinesterase (AChE) (Kawashima and Fujii, 2003). It has been postulated that an LPS challenge is interpreted by the brain as a stressor, causing changes in central neurotransmitter release (Anisman et al., 1993). Acetylcholine (ACh) is a major parasympathetic neurotransmitter and inhibits LPS induced production of proinflammatory cytokines, including IL-1, TNF-α in macrophages (Tracey, 2002) and microglia (Shytle et al., 2004). The levels of ACh are continuously regulated by the hydrolytic enzyme acetyl cholinesterase (AChE), which rapidly degrades ACh. Acetyl cholinesterase inhibitors (AChEIs) increase the availability of ACh in central cholinergic synapses and are the most promising currently available therapy for the treatment of AD. AChEIs are known for their neuroprotective effects other than their major function i.e. choline esterase inhibition, so there may be some more mechanisms of these drugs for their classical functions (Stuchbury and Munch, 2005). AChEIs also protect cells from free radical toxicity (Tabet et al., 2000) and β amyloid-induced injury (Xiao et al., 2000), and increased production of antioxidants (Zhang and Tang, 2000). Increasing evidence now indicate the modulatory role of AChEIs on proinflammatory cytokines in AD patients (Reale et al., 2004) which suggest a link between central cholinergic system and neuroinflammation. Among the cholinergic receptors, both muscarinic and nicotinic receptors are distributed in the CNS and periphery with different synaptic locations and functions in cholinergic transmission. Several reports suggest involvement of cholinergic receptor in neuroprotection against glutamate (Akaike et al., 2006) and β-amyloid induced neurotoxicity (Kihara et al., 2001). Furthermore, epidemiological studies have consistently shown that the incidence of neurodegenerative diseases such as AD and Parkinson’s disease (PD) is lower in cigarette smokers than in age-matched controls (Mihailescu and Drucker, 2000). These findings have prompted speculation that cholinergic nicotinic receptors could be important therapeutic targets for neurodegenerative disorders. Recent reports suggest that electrical or pharmacological activation of the efferent vagus nerve, which activates the release of acetylcholine, inhibits the release of TNF-α and attenuates the development of endotoxin-induced shock in rodents (Borovikova et al., 2000a), has expanded our understanding of how the nervous system modulates immune responses. The association between the cholinergic system and neuroinflammation may provide new direction for the pathogenesis of AD and interaction between the various pathological factors involved in its etiology. The opportunity now exists to apply this insight to the treatment of neuroinflammation through cholinergic up regulation in brain. Therefore the present study was designed to investigate the possible mechanism(s) involved in inhibitory influence of cholinergic enhancers (AChEIs and cholinergic receptor agonists) on neuroinflammation to search the link between cholinergic system and anti-inflammatory functions that may lead to development of a better therapeutic agent for neurodegenerative disorders. |
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2887151 bytes
application/pdf |
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en
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CSIR-CDRI Thesis No. T-38
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| Subject |
Central Cholinergic System
Neuroinflammation Pharmacological Approach |
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| Title |
Relationship between Central Cholinergic System and Neuroinflammation: A Molecular Pharmacological Approach
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| Type |
Thesis
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