Neurochemical & Behavioral Effects of Non Steroidal Antinflammatory Drugs (NSAIDs) in Animal Model of Learned Helplessness.

Abstract

Stress and inflammation are mutually linked processes that encompass many pathological conditions. Inflammation is a body‟s defensive mechanism which is activated in response to tissue injury or infection with the release of inflammatory mediators. Studies on animal models provide useful information regarding psychological and physiological affliction leading to modifications in behavioral, biochemical and neurochemical changes. Stressful events in life often precipitate depressive behaviors, dysfunction metabolic pathways and triggers metabolic syndromes. Stress also encourage generation of oxidative species and reduced activities of endogenous enzyme system, prompts neuronal damages and concomitant development of neurodegenerative diseases. Similarly changes in the neurotransmission system more specifically serotonergic and dopaminergic system have implications on variety of functions ranging from impaired motor coordination, memory deficits, aggression and anhedonia.The present work highlighted effects of stress responses in modulating inflammation when rats were subjected to different psychological and physical stress paradigms such as 2h restraint stress, repeated restraint (2h/day for 5 days) stress and dissimilar stress. Antiinflammatory approaches by the use of non selective NSAIDs (indomethacin and diclofenac sodium) were used to identify possible mechanism of actions of these drugs in the reduction of stress induced inflammatory responses and treatment of stress associated neurological disorders in animal models of stress. Important findings of the thesis are as per the following: 1. The primary finding of present study revealed that repeated administration of indomethacin and diclofenac sodium improved behavioral functions in rats suggesting neuromodulatory effects of NSAIDs on central nervous system. 2. Exposure to 2h restraint stress causes behavioral deficits in the form of reduced exploratory activity, anxiogenic and depressive behaviors in rats. Whereas, augmented memory functions were observed after 2h restraint stress. Pretreatment xxiv with indomethacin and diclofenac sodium was found to normalized 2h restraint stress related alterations in rats when compared with unrestrained rats. 3. Following repeated restraint (2h/day for 5 days) stress both adaptive and maladaptive changes were observed in rats. The adaptive responses as observed on exploratory activity and anxiety states were comparable in restrained rats as compared to unrestrained rats. However, the maladaptive outcomes due to repeated restraint stress were observed in the form of depressive behaviors and decline in memory functions. Indomethacin and diclofenac sodium improved behaviors in rats exposed to repeated restraint stress. 4. Rats exposed to dissimilar stress showed marked behavioral deficits. Continuous exposure to a variety of stressors also served as a model of depression in animals. Indomethacin and diclofenac sodium showed improvement in behaviors. This suggests the role of NSAIDs as a potential therapeutic agent against a variety of neurological disorders. 5. An episode of 2h restraint stress, repeated restraint (2h/day for 5 days) stress and dissimilar stress showed alterations in corticosterone, glucose and cholesterol levels. Our results indicate that these biochemical changes were successfully attenuated by the administration of indomethacin and diclofenac sodium. 6. The study was further aimed to investigate the effect of 2h restraint, repeated restraint (2h/day for 5 days) and dissimilar stress exposure on the oxidative status and also on the activities of antioxidant enzymes (SOD,CAT and GPx) in rat‟s brain. Both indomethacin and diclofenac sodium decreased lipid peroxidation and enhanced functions of endogenous antioxidant enzymes system. This suggests antioxidant properties of these drugs against a variety of stressors. 7. In present study acetylcholinesterase enzyme activity on exposure to 2h restraint stress, repeated restraint (2h/day for 5 days) stress and dissimilar stress showed changes in cholinergic functions in rats. Indomethacin and diclofenac sodium was xxv found to inhibit activity of AChE enzyme similar to those of AChE inhibitors and hence improved memory functions of rats in stress conditions. 8. The study also revealed effect of 2h restraint stress, repeated restraint (2h/day for 5 days) stress and dissimilar stress situations on neurotransmitters levels in rats. Variable results were observed such as increased or decreased serotonergic or dopaminergic activities on exposure to various stress situations. The changes in neurotransmitters also reflected impairments in behavioral activities in rats. Indomethacin and diclofenac sodium was found to normalize the disturbed activities of neurotransmitters in rats. The study tends to suggest that non steroidal antiinflammatory drugs might be used for several stress related pathological features of the central nervous system (CNS). As these drugs have an overall positive outcomes as observed in present thesis by improving the general behaviors, reducing oxidative stress and increasing the levels of serotonergic and dopaminergic neurotransmitters in brain and could be effective to prevent neurological changes accompanied with stress.