Department of Pharmacy
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Item Depression: Current Therapy and ovel Anti-depressant Drug Targets(Pharmacologyonline, 2009) Mahesh, R.Affective disorders such as depression and anxiety are a major cause of disability and place a burden on society from both economic and social perspectives. In spite of over 50 years of effort in drug discovery and development, a substantial increase in the efficacy of antidepressant therapies has not been achieved, although improvements in safety and tolerability have been observed in newer drug therapies. Despite the advances in the anti-depressant therapy with various serotonergic and noradrenergic agents, a substantial unmet medical need in the treatment of depressive illness remains. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas. At one end of the spectrum is combination therapies that maintain the benefits associated with standard anti-depressant drugs and at the other end more novel targets, such as neurotrophins (BDNF, IGF), based on recent findings that antidepressants induce neurogenesis could fit to the need of antidepressant therapy. This review summarizes the pathological detail of depression, current anti-depressant therapy and development of non-monoamine-based antidepressants, and provides a progress report on some of the most promising current strategiesItem Depression Associated Disorders: Comorbidity, eurobiological and eurobehavioural Link(Pharmacologyonline, 2010) Mahesh, R.Comorbidity commonly refers to the co-occurrence (or dual diagnosis) of two disorders or syndromes in the same patient, regardless of whether the disorders are coincidentally or causally linked. Indeed, illnesses have been classified in discrete diagnostic categories although no sharp discontinuities in symptom distributions are observed across most mental disorders. Depression is a relatively common psychiatric comorbididy of most neurological disorders, with prevalence rates ranging between 20 and 50% among patients with stroke, multiple sclerosis, epilepsy, Parkinson’s disease and dementia. Furthermore, depression is an independent predictor of poor quality of life in these patients and has a negative impact on the response to treatment, course and recovery of neurological deficits. Comorbid depressive disorders in neurologic patients can be indistinguishable to the primary mood disorders and may mimic major depression, dysthymic, minor depressive, and bipolar disorders described in the DSM-IV classification of mood disorders. In addition, the great overlap of medical and psychiatric symptoms in depression and neurologic disorders may lead to both false-positive and false-negative diagnoses of depression. Patient with comorbid condition have lower response rate and /or a longer time to response, greater reports of side effect early in treatment and greater likely hood of dropping out. In this review, we focus on comorbid disorder associated with depression.Item Effect of a novel 5-HT3 receptor antagonist carboxamide, 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) on the acute and chronic rodent models of depression(IJPPS, 2013) Mahesh, R.Objective: 5-HT3 receptor the only type of ion channel among the family of serotonergic receptors which is recognized as a potential novel therapeutic target for depression, anxiety and cognition. In the present work was designed to evaluate the antidepressant-like effect of a novel 5-HT3 antagonist carboxamide, 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) in a battery of behavioral acute and chronic rodent models of depression. Methods: Behavioral models with high predictive validities like forced swim test (FST) and tail suspension test (TST) in mice along with mechanistic models including 5-hydroxytryptamine (5-HTP) induced head twich response in mice and reserpine induced hypothermia in rats were used for screening QCM-4. Chronic surgical model of olfactory balbectomy (OBX) was performed and further evaluated by sucrose preference test and open field test (OFT) for anti-depressant like effect of QCM-4. Results: Following were the principle findings in the present research; Firstly, QCM-4 dose dependently reduced the immobility duration in FST and TST. Secondly, in the mechanistic models, QCM-4 dose dependently potentiated 5-HTP induced head twich response and attenuated the reserpine induced hypothermia. Lastely, in the surgical OBX model, QCM-4 reversed the anhedonia and behavioral alterations in animals which was evaluated by increase in the sucrose consumption and reduction in ambulation, fecal contents as well as number of rearings in OFT by QCM-4 treated OBX animals compared to OBX control. Conclusion: The results of the present study, indicates that QCM-4, a novel 5-HT3 receptor antagonist exhibit an anti-depressant like effect. Our further studied will be focused on the chronic unpredictable mild stress induced alterations and molecular mechanism involved in the anti-depressant like action of QCM-4.Item Antidepressant- and anxiolytic-like effect of novel 5-hydroxytryptamine3 receptor antagonist 2-[4-(3-chlorophenyl) piperazin-1-yl]-1,8-naphthyridine -3-carboxylic acid (7e)- An approach using rodent behavioral antidepressant and anxiolytic test battery(Wolters Kluwer, 2016-06) Mahesh, R.Depression and anxiety are among the most common and prevalent forms of mental disorder. The 5-hydroxytryptamine3 (5-HT 3) receptor antagonists modulate serotonergic pathways and show antidepressant- and anxiolytic-like effect in various animal models of depression. The present study was designed to investigate the antidepressant and anxiolytic potential of 2-[4-(3-chlorophenyl) piperazin-1-yl]- 1,8-naphthyridine-3-carboxylic acid (7e), a novel 5-HT 3 receptor antagonist in rodent behavioral models of depression and anxiety.Item Role of Serotonin Type-1A/B (Hydroxytryptamine) Receptors in Depression Revisited(Systematic Reviews in Pharmacy, 2014-04) Mahesh, R.Depression is among the common psychiatric disorders, therefore the common pathways and pathogenesis associated with depression is required to be studied. In few years, role of 5-hydroxytryptamine-1A/B (5-HT1A/B) receptors in depressive disorders have been revealed. Both preclinical and clinical studies reported that the potential agonist and antagonist at 5-HT1A/B receptors have significant modulatory effects in depression. However, the collective details regarding the involvement of 5-HT1A/B receptors and the molecular pathways associated in depression is lacking. Thus, the present review evidence the link between 5-HT1A/B receptors in the brain and depression, the possible pathways involved and their alterations in depression. Further, it reviews the preclinical evidences of 5-HT1A/B receptor modulators as antidepressant agents and their effectiveness. The current review also details the clinical relevance of 5-HT1A/B receptors etiopathogenesis of major depression in humans.Item Evaluation of Anti-depressant and Analgesic- Like Activity of Ondansetron in Rodents Model of Co-morbid Pain and Depression(IJPER, 2015-02) Mahesh, R.; Yadav, SushilAlthough a clinical connection between pain and depression has long been recognized, how these two conditions interact remains unclear. Here we report the comorbidity of pain and depression-like behavior. The antidepressant and analgesic like activity of Ondansetron (OND, 0.25-2mg/kg) were investigated in animal models of acute depression (forced swim test ) and pain ( tail flick test) , existence of co-morbidity of pain and depression was simulated in surgical models in rats like olfactory bulbectomy (OBX) model of chronic depression and chronic constrictive injury (CCI) of chronic pain conditions. Acute administration of OND (0.5-2mg/kg i.p) significantly reduced the duration of immobility in mice in FST and increased the time latency in tail flick test. Behavioural anomalies shown by OBX rats in open field test was significantly reversed by OND (1-2 mg/kg p.o) but OBX rats failed to show the any kind of nociception. Further OND successfully reversed pain in CCI rats. In addition to reversal of pain, OND (1-2mg/kg p.o) significantly reduced the hyperactivity exhibited by CCI rats in open field test suggesting the effect of OND in co-morbid pain and depression. OND exhibited significant antidepressant and analgesic like effect as indicated by its ability to reduce swim stress induced immobility and reduction in writhing. The present study showed that OND has equal efficacy in comorbid pain and depression-like behavioural mediated through serotonergic system.Item Antidepressant-like effect of a novel 5-HT3 receptor antagonist N-(benzo[d] thiazol-2-yl)-3-ethoxyquinoxalin-2-carboxamide 6k using rodents behavioral battery tests(Sage, 2014-09) Mahesh, R.To investigate the antidepressant-like effect of N-(benzo[d] thiazol-2-yl)-3- ethoxyquinoxalin-2-carboxamide 6k, a 5-hydroxytryptamine type 3 (5-HT3) receptor antagonist using rodents behavioral battery tests.Item Antidepressant & anxiolytic activities of N-(pyridin-3-yl) quinoxalin-2-carboxamide: A novel serotonin type 3 receptor antagonist in behavioural animal models(IJMR, 2016) Mahesh, R.Alteration in the serotonin leads to the psychological illness, such as depression, anxiety, schizophrenia, eating disorders, obsessive-compulsive disorder, panic disorders and migraines. The objective of the current study was to investigate the antidepressant and anxiolytic activities of N-(pyridin-3-yl) quinoxalin-2-carboxamide (QCF-21), a novel 5-HT3 receptor antagonist in preclinical models of depression and anxiety.Item Evaluation of Anti-depressant and Analgesic- Like Activity of Ondansetron in Rodents Model of Co-morbid Pain and Depression(IJPER, 2015-02) Mahesh, R.; Yadav, SushilAlthough a clinical connection between pain and depression has long been recognized, how these two conditions interact remains unclear. Here we report the comorbidity of pain and depression-like behavior. The antidepressant and analgesic like activity of Ondansetron (OND, 0.25-2mg/kg) were investigated in animal models of acute depression (forced swim test ) and pain ( tail flick test) , existence of co-morbidity of pain and depression was simulated in surgical models in rats like olfactory bulbectomy (OBX) model of chronic depression and chronic constrictive injury (CCI) of chronic pain conditions. Acute administration of OND (0.5-2mg/kg i.p) significantly reduced the duration of immobility in mice in FST and increased the time latency in tail flick test. Behavioural anomalies shown by OBX rats in open field test was significantly reversed by OND (1-2 mg/kg p.o) but OBX rats failed to show the any kind of nociception. Further OND successfully reversed pain in CCI rats. In addition to reversal of pain, OND (1-2mg/kg p.o) significantly reduced the hyperactivity exhibited by CCI rats in open field test suggesting the effect of OND in co-morbid pain and depression. OND exhibited significant antidepressant and analgesic like effect as indicated by its ability to reduce swim stress induced immobility and reduction in writhing. The present study showed that OND has equal efficacy in comorbid pain and depression-like behavioural mediated through serotonergic system.Item Chronic unpredictable stressors can produce a situation similar to human depression and such animal models can be used for the preclinical evaluation of antidepressants. The 5-HT3 receptor antagonists modulate serotonergic pathways and show antidepressant-like effect in various animal models of depression(NISCAIR, 2013) Mahesh, R.The compound 6o (at 0.5, 1 and 2 mg/kg, ip) with optimum log P and pA2 value, was subjected to forced swim test (FST) and tail suspension test (TST). The compound 6o significantly reduced the duration of immobility in mice without affecting the base line locomotion in actophotometer. Moreover, 6o (2 mg/kg, ip), potentiated the 5-hydroxytryptophan (5-HTP)-induced head twitch responses in mice and at 1 and 2 mg/kg, ip antagonized the reserpine-induced hypothermia (RIH) in rats. In interaction studies with various standard drugs/ligands using FST, 6o (1 and 2 mg/kg, ip) potentiated the anti-depressant effect fluoxetine (5 mg/kg, ip) and reversed the depressant effect of parthenolide (1 mg/kg, ip) by reducing the duration of immobility. Furthermore, 6o (1 and 2 mg/kg, ip) potentiated the effect of bupropion (10 mg/kg, ip) in TST. The behavioural anomalies of the olfactory bulbectomised (OBX) rats were augmented by chronic 6o (1 and 2 mg/kg) treatment as observed from the modified open field test (parameters: ambulation, rearing, fecal pellet). The results suggest that compound 6o exhibited anti-depressant like effect in rodent models of depression.