Yeshwant Kurhe - Academia.edu (original) (raw)

Papers by Yeshwant Kurhe

Research paper thumbnail of Anxiolytic Effect of a Novel 5-HT3 Receptor Antagonist (4-Phenylpiperazin-1-yl) (Quinoxalin-2-yl) Methanone (4a) in a Battery of Behavioral Models for Anxiety in Mice

The Pharma Innovation Journal, 2013

The serotonergic system of brain is well understood to play a crucial role in emotional processin... more The serotonergic system of brain is well understood to play a crucial role in emotional processing in human and animals. 5-HT3 receptor, the ion channel type of receptor is involved in mood, anxiety, depression, learning and memory. Objective of the present work was to investigate the anxiolytic potential of a novel 5-HT3 receptor antagonist (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a) in mice. Different behavioral test paradigms for anxiety like elevated plus maze, open field test, light-dark model and hole board test were used for assessing the effect. Diazepam 2 mg/kg i.p. served as a reference standard. From the results it was found that 4a dose dependently at 2 and 4 mg/kg i.p. attenuated the behavioral alterations in the anxiety models in mice. The exact mechanism of 5HT3 receptor antagonist for anxiolytic potential is still ill understood. Our further studies will deal with mechanisms at molecular levels for anxiolytic potential of 4a. Keyword: 5-HT3 Receptor, An...

Research paper thumbnail of Antagonizing STK25 Signaling Suppresses the Development of Hepatocellular Carcinoma Through Targeting Metabolic, Inflammatory, and Pro-Oncogenic Pathways

Cellular and Molecular Gastroenterology and Hepatology, 2021

This study provides evidence that antagonizing STK25 signaling hinders the development of NASH-re... more This study provides evidence that antagonizing STK25 signaling hinders the development of NASH-related HCC and provides an impetus for further analysis of STK25 as a therapeutic target for NASH-induced HCC treatment in human beings.

Research paper thumbnail of STE20-Type Protein Kinase MST4 Controls NAFLD Progression by Regulating Lipid Droplet Dynamics and Metabolic Stress in Hepatocytes

Hepatology Communications, 2021

Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease ... more Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide, primarily because of the massive global increase in obesity. Despite intense research efforts in this field, the factors that govern the initiation and subsequent progression of NAFLD are poorly understood, which hampers the development of diagnostic tools and effective therapies in this area of high unmet medical need. Here we describe a regulator in molecular pathogenesis of NAFLD: STE20-type protein kinase MST4. We found that MST4 expression in human liver biopsies was positively correlated with the key features of NAFLD (i.e., hepatic steatosis, lobular inflammation, and hepatocellular ballooning). Furthermore, the silencing of MST4 attenuated lipid accumulation in human hepatocytes by stimulating β-oxidation and triacylglycerol secretion, while inhibiting fatty acid influx and lipid synthesis. Conversely, overexpression of MST4 in human hepatocytes exacerbated fat deposit...

Research paper thumbnail of Lipid droplet-associated kinase STK25 regulates peroxisomal activity and metabolic stress response in steatotic liver

Journal of Lipid Research, 2019

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as ... more Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide and have been recognized as one of the major unmet medical needs of the 21st century. Our recent translational studies in mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine kinase (STK)25 as a protein that coats intrahepatocellular lipid droplets (LDs) and critically regulates liver lipid homeostasis and progression of NAFLD/NASH. Here, we studied the mechanism-of-action of STK25 in steatotic liver by relative quantification of the hepatic LD-associated phosphoproteome from high-fat diet-fed Stk25 knockout mice compared with their wild-type littermates. We observed a total of 131 proteins and 60 phosphoproteins that were differentially represented in STK25-deficient livers. Most notably, a number of proteins involved in peroxisomal function, ubiquitination-mediated proteolysis, and antioxidant ...

Research paper thumbnail of Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans

The FASEB Journal, 2019

Ectopic lipid storage in the liver is considered the main risk factor for nonalcoholic steatohepa... more Ectopic lipid storage in the liver is considered the main risk factor for nonalcoholic steatohepatitis (NASH). Understanding the molecular networks controlling hepatocellular lipid deposition is therefore essential for developing new strategies to effectively prevent and treat this complex disease. Here, we describe a new regulator of lipid partitioning in human hepatocytes: mammalian sterile 20-like (MST) 3. We found that MST3 protein coats lipid droplets in mouse and human liver cells. Knockdown of MST3 attenuated lipid accumulation in human hepatocytes by stimulating b-oxidation and triacylglycerol secretion while inhibiting fatty acid influx and lipid synthesis. We also observed that lipogenic gene expression and acetyl-coenzyme A carboxylase protein abundance were reduced in MST3-deficient hepatocytes, providing insight into the molecular mechanisms underlying the decreased lipid storage. Furthermore, MST3 expression was positively correlated with key features of NASH (i.e., hepatic lipid content, lobular inflammation, and hepatocellular ballooning) in human liver biopsies. In summary, our results reveal a role of MST3 in controlling the dynamic metabolic balance of liver lipid catabolism vs. lipid anabolism. Our findings highlight MST3 as a potential drug target for the prevention and treatment of NASH and related complex metabolic diseases.

Research paper thumbnail of Ondansetron ameliorates depression associated with obesity in high-fat diet fed experimental mice: An investigation-based on the behavioral, biochemical, and molecular approach

Indian journal of pharmacology

Obesity is an important risk factor for depression as more than half of the obese population is s... more Obesity is an important risk factor for depression as more than half of the obese population is susceptible for depression at double rate. Our earlier studies reported the antidepressant potential of 5-HT receptor antagonist, ondansetron (OND) in depression associated obesity using behavioral tasks. The present research work is aimed to evaluate the effect of OND on depression associated with obesity with special emphasis on biochemical and molecular mechanisms such as hippocampal brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate (cAMP), 5-hydroxytryptamine (5-HT), hippocampal histological examination and immunohistochemical expression of p53 proteins. Mice were fed with high-fat diet (HFD) for 14 weeks, followed by treatment schedule for 28 days with vehicle/OND (0.5 and 1 mg/kg, p.o.)/reference antidepressant escitalopram (10 mg/kg, p.o.). Subsequently, animals were screened in the behavioral tests of depression such as forced swim test (FST) and sucrose pre...

Research paper thumbnail of Novel 5-HT3 receptor antagonist QCM-4 attenuates depressive-like phenotype associated with obesity in high-fat-diet-fed mice

Psychopharmacology, 2017

Depression associated with obesity remains an interesting area to study the biological mechanisms... more Depression associated with obesity remains an interesting area to study the biological mechanisms and novel therapeutic intervention. The present study investigates the effect of a novel 5-HT3 receptor antagonist 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) on several pathogenic markers of depression associated with obesity such as plasma insulin resistance, hippocampal cyclic adenosine monophosphate (cAMP), brain-derived neurotrophic factor (BDNF), serotonin (5-HT) concentrations, hippocampal neuronal damage, and p53 protein expression in high-fat-diet (HFD)-fed mice. Obesity was experimentally induced in mice by feeding with HFD for 14 weeks followed by administration of QCM-4 (1 and 2 mg/kg, p.o.)/standard escitalopram (ESC) (10 mg/kg, p.o.)/vehicle (10 ml/kg, p.o.) for 28 days. Behavioral assays such as sucrose preference test (SPT); forced swim test (FST); elevated plus maze (EPM); biochemical assays including oral glucose tolerance tests (OGTT), insulin, cAMP, BDNF, and...

Research paper thumbnail of Pioglitazone, a PPARγ agonist rescues depression associated with obesity using chronic unpredictable mild stress model in experimental mice

Neurobiology of Stress, 2016

Pioglitazone, a peroxisome proliferator activated receptor gamma (PPARg) agonist belonging to thi... more Pioglitazone, a peroxisome proliferator activated receptor gamma (PPARg) agonist belonging to thiazolidinedione class, is mainly used in diabetes mellitus. Obese subjects are twice likely to become depressed than non-obese individuals. The biological mechanisms linking depression with obesity still remain poorly understood and there is immense need for better therapeutic intervention against such co-morbid disorders. The present study investigates the effect of pioglitazone on the chronic unpredictable mild stress (CUMS) induced depression in obese mice by using behavioral tests and biochemical estimations. Mice were fed with high fat diet (HFD) for 14 weeks and were further subjected to different stress procedures for 28 days to induce depressive behavior. Animals were administered orally with pioglitazone (30 mg/kg p.o.)/escitalopram (10 mg/kg p.o.)/vehicle (10 ml/kg p.o.) daily from day 15e28. Various behavioral paradigms such as sucrose preference test, forced swim test (FST), tail suspension test (TST) and elevated plus maze (EPM) were performed. Biochemical estimations including plasma glucose, total cholesterol, triglycerides, and total proteins were performed. The data obtained from behavioral assays and biochemical assessments indicated that obese animals exhibited severe depressive-like behavior compared to non-obese animals. Furthermore, obese animals subjected to CUMS worsen the depressive behavior compared to obese control animals. Repetitive treatment with pioglitazone reversed the CUMS induced behavioral and biochemical alterations in HFD fed obese mice which atleast in part may be mediated through improving altered plasma glucose. The study suggests that pioglitazone needs further attention with respect to molecular mechanisms that could provide a better therapeutic strategy against depression associated with obesity.

Research paper thumbnail of Mechanisms linking depression co-morbid with obesity: An approach for serotonergic type 3 receptor antagonist as novel therapeutic intervention

Asian Journal of Psychiatry, 2015

Research paper thumbnail of Effect of a Novel 5-HT3 Receptor Antagonist 3-METHOXY-N-P-TOLYLQUINOXALIN-2- Carboxamide (QCM-4) on the Acute and Chronic Rodent Models of Depression

International Journal of Pharmacy and Pharmaceutical Sciences

Objective: 5-HT3 receptor the only type of ion channel among the family of serotonergic receptors... more 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 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, QC...

Research paper thumbnail of Pharmacological evaluation of novel 5-HT3 receptor antagonist, QCM-13 (N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) as anti-anxiety agent in behavioral test battery

Journal of pharmacy & bioallied sciences

In the last few decades, serotonin type-3 (5-HT3) receptor antagonists have been identified as po... more In the last few decades, serotonin type-3 (5-HT3) receptor antagonists have been identified as potential targets for anxiety disorders. In preclinical studies, 5-HT3 antagonists have shown promising antianxiety effects. In this study, a novel 5-HT3 receptor antagonist, QCM-13(N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) was evaluated for anxiolytic-like activity in rodent behavioral test battery. Mice were given QCM-13 (2 and 4 mg/kg, intraperitoneally [i.p.]) or diazepam (2 mg/kg, i.p.) or vehicle and after 30 min, mice were subjected to four validated behavioral test batteries viz. elevated plus maze, hole board, light-dark and open field tests. Interaction study of QCM-13 with m-chlorophenyl piperazine (mCPP) (mCPP, a 5-HT2A/2C receptor agonist, 1 mg/kg, i.p.) and buspirone (BUS, a partial 5-HT1A agonist, 10 mg/kg, i.p.) were performed to assess the pharmacological mechanism of the drug. QCM-13 expressed potential anxiolytic effect with significant (P < 0.05) increase in be...

Research paper thumbnail of Ondansetron, a 5HT3 receptor antagonist reverses depression and anxiety-like behavior in streptozotocin-induced diabetic mice: Possible implication of serotonergic system

European Journal of Pharmacology, 2014

Increased prevalence and high comorbidity of depression-like mood disorders and diabetes have pro... more Increased prevalence and high comorbidity of depression-like mood disorders and diabetes have prompted investigation of new targets and potential contributing agents. There is considerable evidence supporting the inconsistent clinical efficacy and persistent undesirable effects of existing antidepressant therapy for depression associated with diabetes. Therefore, the present study was aimed at investigating the effect of ondansetron, a selective 5HT3 receptor antagonist in attenuating depression and anxiety-like behavior comorbid with diabetes. Experimentally, Swiss albino mice were rendered diabetic by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 200 mg/kg). After 8 weeks, diabetic mice received a single dose of vehicle/ondansetron (0.5 and 1 mg/kg, p.o.)/fluoxetine (the positive control, 10 mg/kg p.o.) for 28 days. Thereafter, behavioral studies were conducted to test depression-like behavior using forced swim test (FST) and anxiety-like deficits using hole-board and light-dark tests, followed by biochemical estimation of serotonin content in discrete brain regions. The results demonstrated that, STZ-induced diabetic mice exhibited increased duration of immobility and decreased swimming behavior in FST, reduced exploratory behavior during hole-board test and increased aversion to brightly illuminated light area in light-dark test as compared to non-diabetic mice, while ondansetron (similar to fluoxetine) treatment significantly reversed the same. Biochemical assay revealed that ondansetron administration attenuated diabetes-induced neurochemical impairment of serotonin function, indicated by elevated serotonin levels in discrete brain regions of diabetic mice. Collectively, the data indicate that ondansetron may reverse depression and anxiety-like behavioral deficits associated with diabetes in mice and modulation of serotonergic activity may be a key mechanism of the compound.

Research paper thumbnail of QCM-4, a serotonergic type 3 receptor modulator attenuates depression co-morbid with obesity in mice: An approach based on behavioral and biochemical investigations

European Journal of Pharmacology, 2014

Previous studies in our laboratory examined the antidepressant potential of 3-methoxy-N-p-tolylqu... more Previous studies in our laboratory examined the antidepressant potential of 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4), a 5-HT 3 receptor antagonist in acute and chronic rodent models of depression. The aim of present study was to investigate the effect of QCM-4 on chronic unpredictable mild stress (CUMS) induced depression in obese mice using behavioral based battery tests and biochemical assessments. Depressive behavior was induced in obese mice by subjecting to different stress procedures for 28 days. The results indicated that the CUMS induced severe depressive behavior in obese mice as demonstrated by a significant decreased sucrose consumption, increased immobility time in forced swim test (FST) and tail suspension test (TST), decreased percent entries and time in open arm in elevated plus maze (EPM). Moreover, CUMS significantly increased the plasma glucose, total cholesterol, triglycerides and total proteins in obese mice. Chronic treatment with QCM-4 (2 mg/kg po) and standard drug escitalopram (10 mg/kg po) significantly reversed the depressive behavioral changes (increased sucrose consumption, decreased immobility time in FST and TST, and increased the percent entries and time in open arm in EPM) and biochemical alterations (reversed the raised levels of plasma glucose, total cholesterol, triglycerides and total proteins) in obese mice subjected to CUMS. No alteration was observed in the locomotor score in obese mice. In conclusion, the results of the present study suggested that QCM-4 attenuated the depression co-morbid with obesity in mice subjected to CUMS which to some extent is mediated by reversing the "insulin resistance" or "altered plasma glucose" in obese mice.

Research paper thumbnail of 5HT3 receptor antagonist (ondansetron) reverses depressive behavior evoked by chronic unpredictable stress in mice: Modulation of hypothalamic–pituitary–adrenocortical and brain serotonergic system

Pharmacology Biochemistry and Behavior, 2014

Chronic stress is one of the major causes of depression, associated with behavioral and biochemic... more Chronic stress is one of the major causes of depression, associated with behavioral and biochemical impairments. 5HT3 receptor antagonists (such as ondansetron) have shown alleviation of depressive symptomology in preclinical and in few clinical studies. However, their effects in chronic stress-induced depressive behavior and the underlying mechanism(s) are yet to be known. In the present study, the effects of a 5HT3 receptor antagonist, ondansetron were evaluated in chronic unpredictable stress (CUS)-evoked depressive behavior. In addition, the possible mechanism was determined by measuring plasma corticosterone (CORT) as a marker of hypothalamic-pituitary-adrenocortical (HPA)-axis activity and serotonin levels in the discrete brain regions. Mice were subjected to a battery of unpredictable stressors for 28 days. Ondansetron (0.05, 0.1 and 1mg/kg, p.o.) and fluoxetine (10mg/kg, p.o.) were administered during the last 14 days (day 15-28th) of CUS testing paradigm. The results showed that the 4-week CUS produced significant depressive behavior in mice, which included increased despair effects in forced swim test (FST) and reward-related deficits in sucrose preference test. Biochemical assays demonstrated a significant increase in percentage of plasma CORT and decrease in percentage of serotonin levels in the discrete brain regions of CUS mice. Chronic ondansetron treatment, similar to that of positive control fluoxetine, significantly reversed despair effects in FST and reward-related deficits in sucrose preference test. In addition, ondansetron and fluoxetine treatments significantly increased percentage of serotonin levels in the measured brain regions and attenuated HPA-axis hyperactivity, as evidenced by low percentage of plasma CORT levels in CUS mice. These findings indicate the potential role of ondansetron (a 5HT3 receptor antagonist) in reversing CUS-induced depressive behavior, which is possibly mediated by its modulating effects on the HPA-axis and serotonergic system. Further, the study represents that 5HT3 receptor antagonists can be a potential therapeutic candidate for stress-related depressive disorders.

Research paper thumbnail of Effect of a novel 5-HT3 receptor antagonist 4i, in corticosterone-induced depression-like behavior and oxidative stress in mice

Steroids, 2015

Stress in our daily life severely affects the normal physiology of the biological system. Dysregu... more Stress in our daily life severely affects the normal physiology of the biological system. Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the development of depression-like behavior, which remains under diagnosed and poorly treated. Exogenous corticosterone (CORT) administration has been demonstrated to develop a depression model, which has shown to mimic HPA-axis induced depression-like state in rodents. In the present study, the effect of a novel 5HT 3 receptor, 4i was examined on CORT induced depression in mice. CORT (30 mg/kg, subcutaneously) was given for 4-weeks to mice in control group, while mice in drug treated group were given 4i (0.5-1 mg/kg, intraperitoneally)/fluoxetine (as a positive control, 10 mg/kg), for the last 2-weeks of CORT dosing. Repeated CORT dosing caused depression-like behavior in mice as indicated by increased despair effects in forced swim test (FST) and anhedonia in sucrose preference test. In addition, CORT administration induced oxidative load in the brain with significant increase in pro-oxidant (lipid peroxidation and nitrite levels) markers and a substantial decline in anti-oxidant defense (catalase and reduced glutathione levels) system, indicating a direct effect of stress hormones in the induction of the brain oxidative damage. On the other hand, 4i and fluoxetine treatment reversed the CORT induced depressive-like deficits. Furthermore, 4i and fluoxetine prevented CORT induced oxidative brain insults, which may plausibly demonstrate one of the key mechanisms for antidepressant-like effects of the compounds. Thus, the study suggests that 5HT 3 antagonist; 4i may be implicated as pharmacological intervention targeting depressive-like anomaly associated with HPA-axis dysregulation.

Research paper thumbnail of Anxiolytic-like effects of alverine citrate in experimental mouse models of anxiety

European Journal of Pharmacology, 2014

Anxiety disorders are widely spread psychiatric illnesses that are a cause of major concern. Desp... more Anxiety disorders are widely spread psychiatric illnesses that are a cause of major concern. Despite a consistent increase in anxiolytics, the prevalence of anxiety is static; this necessitates the development of new compounds with potential activity and minimum unwanted effects. A serotonergic (5HT) system plays an important role in pathogenesis of anxiety and predominantly involves 5HT 1A receptor action in mediating anxiety-like behavior; the antagonism of 5HT 1A receptor has demonstrated to produce anxiolytic-like effects. Alverine citrate (AVC) is reported as a 5HT 1A antagonist; however, its effects on anxiety-like behavior are not investigated. Thus, the present study, by utilizing a neurobehavioral approach, examined the anxiolytic-like effects of AVC in experimental mouse models of anxiety. Mice were acutely treated with AVC (5-20 mg/kg, i.p.)/diazepam (DIA, 2 mg/kg, i.p.) and subjected to four validated anxiety models viz. elevated plus-maze (EPM), light/dark (L/D), hole-board (HB) and marble burying (MB) tests. AVC (15-20 mg/kg) and DIA significantly increased open arm activity in EPM, exploration in light chamber in L/D test, exploratory behavior in HB and reduced MB behavior in marble burying test. AVC (5 mg/kg) had no effect on all behavioral tests, while AVC (10 mg/kg) produced partial effects. It revealed anxiolytic-like effects of AVC. Furthermore, anxiolytic-like effects of AVC at higher doses (15-20 mg/kg) were more pronounced than lower doses (10 mg/kg) and were quite similar to the standard drug DIA. The present finding demonstrates, for the first time, the anxiolytic-like effects of AVC, which may be an alternative approach for management of anxiety-related disorders.

Research paper thumbnail of Ondansetron attenuates depression co-morbid with obesity in obese mice subjected to chronic unpredictable mild stress; an approach using behavioral battery tests

Metabolic Brain Disease, 2014

Research paper thumbnail of A novel animal model of metabolic syndrome with non-alcoholic fatty liver disease and skin inflammation

Pharmaceutical biology, Jan 28, 2014

Context: Metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) are the emerging co-mor... more Context: Metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) are the emerging co-morbidities of skin inflammation. Occurrence of skin inflammation such as psoriasis is substantially higher in NAFLD patients than normal. Currently, there are no animal models to study the interaction between these co-morbidities. Objective: The present study seeks to develop a simple mouse model of NAFLD-enhanced skin inflammation and to study the effect of NAFLD on different parameters of skin inflammation. Materials and method: Metabolic syndrome and NAFLD were induced in C57BL/6 mice by feeding high-fat diet (HFD, 60% kcal) and high fructose liquid (HFL, 40% kcal) in drinking water. Skin inflammation was induced by repeated application of oxazolone (1% sensitization and repeated 0.5% challenge) in both normal and NAFLD mice and various parameters of skin inflammation and NAFLD were measured. Results: HFD and HFL diet induced obesity, hyperglycemia, hyperinsulinemia, and histological fe...

Research paper thumbnail of Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression

Acta pharmacologica Sinica, 2014

To investigate the antidepressant-like effects of a novel 5-HT3 receptor antagonist N-(benzo[d]th... more To investigate the antidepressant-like effects of a novel 5-HT3 receptor antagonist N-(benzo[d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide (6z) in acute and chronic murine models of depression. 5-HT3 receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test (TST) was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z (0.5-2 mg/kg, ip). In chronic depression model, mice were exposed to a 4-week chronic unpredictable stress (CUS) protocol, and treated with 6z (0.5-2 mg·kg(-1)·d(-1), po) or a positive drug fluoxetine (10 mg·kg(-1)·d(-1), po) in the last 2 weeks, followed by behavioral and biochemical assessments. The 5-HT3 receptor antagonism of 6z (pA2=7.4) in guinea pig ileum was more potent than that of a standard 5-HT3 receptor antagonist ondansetron (pA2=6.9). In acute depression model, 6z administration significantly decreased the immobility duration. In chronic depression model, 6z administration re...

Research paper thumbnail of Antidepressant effects of insulin in streptozotocin induced diabetic mice: Modulation of brain serotonin system

Physiology & Behavior, 2014

• STZ induced diabetes resulted in depression in mice. • STZ induced diabetes exhibited decreased... more • STZ induced diabetes resulted in depression in mice. • STZ induced diabetes exhibited decreased serotonin levels in the brain. • Insulin treatment produced an antidepressant effect in STZ induced diabetic mice. • Insulin significantly increased the brain serotonin concentrations. • Thus, insulin could be acting through modulation of the brain serotonin system.

Research paper thumbnail of Anxiolytic Effect of a Novel 5-HT3 Receptor Antagonist (4-Phenylpiperazin-1-yl) (Quinoxalin-2-yl) Methanone (4a) in a Battery of Behavioral Models for Anxiety in Mice

The Pharma Innovation Journal, 2013

The serotonergic system of brain is well understood to play a crucial role in emotional processin... more The serotonergic system of brain is well understood to play a crucial role in emotional processing in human and animals. 5-HT3 receptor, the ion channel type of receptor is involved in mood, anxiety, depression, learning and memory. Objective of the present work was to investigate the anxiolytic potential of a novel 5-HT3 receptor antagonist (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a) in mice. Different behavioral test paradigms for anxiety like elevated plus maze, open field test, light-dark model and hole board test were used for assessing the effect. Diazepam 2 mg/kg i.p. served as a reference standard. From the results it was found that 4a dose dependently at 2 and 4 mg/kg i.p. attenuated the behavioral alterations in the anxiety models in mice. The exact mechanism of 5HT3 receptor antagonist for anxiolytic potential is still ill understood. Our further studies will deal with mechanisms at molecular levels for anxiolytic potential of 4a. Keyword: 5-HT3 Receptor, An...

Research paper thumbnail of Antagonizing STK25 Signaling Suppresses the Development of Hepatocellular Carcinoma Through Targeting Metabolic, Inflammatory, and Pro-Oncogenic Pathways

Cellular and Molecular Gastroenterology and Hepatology, 2021

This study provides evidence that antagonizing STK25 signaling hinders the development of NASH-re... more This study provides evidence that antagonizing STK25 signaling hinders the development of NASH-related HCC and provides an impetus for further analysis of STK25 as a therapeutic target for NASH-induced HCC treatment in human beings.

Research paper thumbnail of STE20-Type Protein Kinase MST4 Controls NAFLD Progression by Regulating Lipid Droplet Dynamics and Metabolic Stress in Hepatocytes

Hepatology Communications, 2021

Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease ... more Nonalcoholic fatty liver disease (NAFLD) has emerged as a leading cause of chronic liver disease worldwide, primarily because of the massive global increase in obesity. Despite intense research efforts in this field, the factors that govern the initiation and subsequent progression of NAFLD are poorly understood, which hampers the development of diagnostic tools and effective therapies in this area of high unmet medical need. Here we describe a regulator in molecular pathogenesis of NAFLD: STE20-type protein kinase MST4. We found that MST4 expression in human liver biopsies was positively correlated with the key features of NAFLD (i.e., hepatic steatosis, lobular inflammation, and hepatocellular ballooning). Furthermore, the silencing of MST4 attenuated lipid accumulation in human hepatocytes by stimulating β-oxidation and triacylglycerol secretion, while inhibiting fatty acid influx and lipid synthesis. Conversely, overexpression of MST4 in human hepatocytes exacerbated fat deposit...

Research paper thumbnail of Lipid droplet-associated kinase STK25 regulates peroxisomal activity and metabolic stress response in steatotic liver

Journal of Lipid Research, 2019

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as ... more Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide and have been recognized as one of the major unmet medical needs of the 21st century. Our recent translational studies in mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine kinase (STK)25 as a protein that coats intrahepatocellular lipid droplets (LDs) and critically regulates liver lipid homeostasis and progression of NAFLD/NASH. Here, we studied the mechanism-of-action of STK25 in steatotic liver by relative quantification of the hepatic LD-associated phosphoproteome from high-fat diet-fed Stk25 knockout mice compared with their wild-type littermates. We observed a total of 131 proteins and 60 phosphoproteins that were differentially represented in STK25-deficient livers. Most notably, a number of proteins involved in peroxisomal function, ubiquitination-mediated proteolysis, and antioxidant ...

Research paper thumbnail of Protein kinase MST3 modulates lipid homeostasis in hepatocytes and correlates with nonalcoholic steatohepatitis in humans

The FASEB Journal, 2019

Ectopic lipid storage in the liver is considered the main risk factor for nonalcoholic steatohepa... more Ectopic lipid storage in the liver is considered the main risk factor for nonalcoholic steatohepatitis (NASH). Understanding the molecular networks controlling hepatocellular lipid deposition is therefore essential for developing new strategies to effectively prevent and treat this complex disease. Here, we describe a new regulator of lipid partitioning in human hepatocytes: mammalian sterile 20-like (MST) 3. We found that MST3 protein coats lipid droplets in mouse and human liver cells. Knockdown of MST3 attenuated lipid accumulation in human hepatocytes by stimulating b-oxidation and triacylglycerol secretion while inhibiting fatty acid influx and lipid synthesis. We also observed that lipogenic gene expression and acetyl-coenzyme A carboxylase protein abundance were reduced in MST3-deficient hepatocytes, providing insight into the molecular mechanisms underlying the decreased lipid storage. Furthermore, MST3 expression was positively correlated with key features of NASH (i.e., hepatic lipid content, lobular inflammation, and hepatocellular ballooning) in human liver biopsies. In summary, our results reveal a role of MST3 in controlling the dynamic metabolic balance of liver lipid catabolism vs. lipid anabolism. Our findings highlight MST3 as a potential drug target for the prevention and treatment of NASH and related complex metabolic diseases.

Research paper thumbnail of Ondansetron ameliorates depression associated with obesity in high-fat diet fed experimental mice: An investigation-based on the behavioral, biochemical, and molecular approach

Indian journal of pharmacology

Obesity is an important risk factor for depression as more than half of the obese population is s... more Obesity is an important risk factor for depression as more than half of the obese population is susceptible for depression at double rate. Our earlier studies reported the antidepressant potential of 5-HT receptor antagonist, ondansetron (OND) in depression associated obesity using behavioral tasks. The present research work is aimed to evaluate the effect of OND on depression associated with obesity with special emphasis on biochemical and molecular mechanisms such as hippocampal brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate (cAMP), 5-hydroxytryptamine (5-HT), hippocampal histological examination and immunohistochemical expression of p53 proteins. Mice were fed with high-fat diet (HFD) for 14 weeks, followed by treatment schedule for 28 days with vehicle/OND (0.5 and 1 mg/kg, p.o.)/reference antidepressant escitalopram (10 mg/kg, p.o.). Subsequently, animals were screened in the behavioral tests of depression such as forced swim test (FST) and sucrose pre...

Research paper thumbnail of Novel 5-HT3 receptor antagonist QCM-4 attenuates depressive-like phenotype associated with obesity in high-fat-diet-fed mice

Psychopharmacology, 2017

Depression associated with obesity remains an interesting area to study the biological mechanisms... more Depression associated with obesity remains an interesting area to study the biological mechanisms and novel therapeutic intervention. The present study investigates the effect of a novel 5-HT3 receptor antagonist 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) on several pathogenic markers of depression associated with obesity such as plasma insulin resistance, hippocampal cyclic adenosine monophosphate (cAMP), brain-derived neurotrophic factor (BDNF), serotonin (5-HT) concentrations, hippocampal neuronal damage, and p53 protein expression in high-fat-diet (HFD)-fed mice. Obesity was experimentally induced in mice by feeding with HFD for 14 weeks followed by administration of QCM-4 (1 and 2 mg/kg, p.o.)/standard escitalopram (ESC) (10 mg/kg, p.o.)/vehicle (10 ml/kg, p.o.) for 28 days. Behavioral assays such as sucrose preference test (SPT); forced swim test (FST); elevated plus maze (EPM); biochemical assays including oral glucose tolerance tests (OGTT), insulin, cAMP, BDNF, and...

Research paper thumbnail of Pioglitazone, a PPARγ agonist rescues depression associated with obesity using chronic unpredictable mild stress model in experimental mice

Neurobiology of Stress, 2016

Pioglitazone, a peroxisome proliferator activated receptor gamma (PPARg) agonist belonging to thi... more Pioglitazone, a peroxisome proliferator activated receptor gamma (PPARg) agonist belonging to thiazolidinedione class, is mainly used in diabetes mellitus. Obese subjects are twice likely to become depressed than non-obese individuals. The biological mechanisms linking depression with obesity still remain poorly understood and there is immense need for better therapeutic intervention against such co-morbid disorders. The present study investigates the effect of pioglitazone on the chronic unpredictable mild stress (CUMS) induced depression in obese mice by using behavioral tests and biochemical estimations. Mice were fed with high fat diet (HFD) for 14 weeks and were further subjected to different stress procedures for 28 days to induce depressive behavior. Animals were administered orally with pioglitazone (30 mg/kg p.o.)/escitalopram (10 mg/kg p.o.)/vehicle (10 ml/kg p.o.) daily from day 15e28. Various behavioral paradigms such as sucrose preference test, forced swim test (FST), tail suspension test (TST) and elevated plus maze (EPM) were performed. Biochemical estimations including plasma glucose, total cholesterol, triglycerides, and total proteins were performed. The data obtained from behavioral assays and biochemical assessments indicated that obese animals exhibited severe depressive-like behavior compared to non-obese animals. Furthermore, obese animals subjected to CUMS worsen the depressive behavior compared to obese control animals. Repetitive treatment with pioglitazone reversed the CUMS induced behavioral and biochemical alterations in HFD fed obese mice which atleast in part may be mediated through improving altered plasma glucose. The study suggests that pioglitazone needs further attention with respect to molecular mechanisms that could provide a better therapeutic strategy against depression associated with obesity.

Research paper thumbnail of Mechanisms linking depression co-morbid with obesity: An approach for serotonergic type 3 receptor antagonist as novel therapeutic intervention

Asian Journal of Psychiatry, 2015

Research paper thumbnail of Effect of a Novel 5-HT3 Receptor Antagonist 3-METHOXY-N-P-TOLYLQUINOXALIN-2- Carboxamide (QCM-4) on the Acute and Chronic Rodent Models of Depression

International Journal of Pharmacy and Pharmaceutical Sciences

Objective: 5-HT3 receptor the only type of ion channel among the family of serotonergic receptors... more 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 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, QC...

Research paper thumbnail of Pharmacological evaluation of novel 5-HT3 receptor antagonist, QCM-13 (N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) as anti-anxiety agent in behavioral test battery

Journal of pharmacy & bioallied sciences

In the last few decades, serotonin type-3 (5-HT3) receptor antagonists have been identified as po... more In the last few decades, serotonin type-3 (5-HT3) receptor antagonists have been identified as potential targets for anxiety disorders. In preclinical studies, 5-HT3 antagonists have shown promising antianxiety effects. In this study, a novel 5-HT3 receptor antagonist, QCM-13(N-cyclohexyl-3-methoxyquinoxalin-2-carboxamide) was evaluated for anxiolytic-like activity in rodent behavioral test battery. Mice were given QCM-13 (2 and 4 mg/kg, intraperitoneally [i.p.]) or diazepam (2 mg/kg, i.p.) or vehicle and after 30 min, mice were subjected to four validated behavioral test batteries viz. elevated plus maze, hole board, light-dark and open field tests. Interaction study of QCM-13 with m-chlorophenyl piperazine (mCPP) (mCPP, a 5-HT2A/2C receptor agonist, 1 mg/kg, i.p.) and buspirone (BUS, a partial 5-HT1A agonist, 10 mg/kg, i.p.) were performed to assess the pharmacological mechanism of the drug. QCM-13 expressed potential anxiolytic effect with significant (P < 0.05) increase in be...

Research paper thumbnail of Ondansetron, a 5HT3 receptor antagonist reverses depression and anxiety-like behavior in streptozotocin-induced diabetic mice: Possible implication of serotonergic system

European Journal of Pharmacology, 2014

Increased prevalence and high comorbidity of depression-like mood disorders and diabetes have pro... more Increased prevalence and high comorbidity of depression-like mood disorders and diabetes have prompted investigation of new targets and potential contributing agents. There is considerable evidence supporting the inconsistent clinical efficacy and persistent undesirable effects of existing antidepressant therapy for depression associated with diabetes. Therefore, the present study was aimed at investigating the effect of ondansetron, a selective 5HT3 receptor antagonist in attenuating depression and anxiety-like behavior comorbid with diabetes. Experimentally, Swiss albino mice were rendered diabetic by a single intraperitoneal (i.p.) injection of streptozotocin (STZ, 200 mg/kg). After 8 weeks, diabetic mice received a single dose of vehicle/ondansetron (0.5 and 1 mg/kg, p.o.)/fluoxetine (the positive control, 10 mg/kg p.o.) for 28 days. Thereafter, behavioral studies were conducted to test depression-like behavior using forced swim test (FST) and anxiety-like deficits using hole-board and light-dark tests, followed by biochemical estimation of serotonin content in discrete brain regions. The results demonstrated that, STZ-induced diabetic mice exhibited increased duration of immobility and decreased swimming behavior in FST, reduced exploratory behavior during hole-board test and increased aversion to brightly illuminated light area in light-dark test as compared to non-diabetic mice, while ondansetron (similar to fluoxetine) treatment significantly reversed the same. Biochemical assay revealed that ondansetron administration attenuated diabetes-induced neurochemical impairment of serotonin function, indicated by elevated serotonin levels in discrete brain regions of diabetic mice. Collectively, the data indicate that ondansetron may reverse depression and anxiety-like behavioral deficits associated with diabetes in mice and modulation of serotonergic activity may be a key mechanism of the compound.

Research paper thumbnail of QCM-4, a serotonergic type 3 receptor modulator attenuates depression co-morbid with obesity in mice: An approach based on behavioral and biochemical investigations

European Journal of Pharmacology, 2014

Previous studies in our laboratory examined the antidepressant potential of 3-methoxy-N-p-tolylqu... more Previous studies in our laboratory examined the antidepressant potential of 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4), a 5-HT 3 receptor antagonist in acute and chronic rodent models of depression. The aim of present study was to investigate the effect of QCM-4 on chronic unpredictable mild stress (CUMS) induced depression in obese mice using behavioral based battery tests and biochemical assessments. Depressive behavior was induced in obese mice by subjecting to different stress procedures for 28 days. The results indicated that the CUMS induced severe depressive behavior in obese mice as demonstrated by a significant decreased sucrose consumption, increased immobility time in forced swim test (FST) and tail suspension test (TST), decreased percent entries and time in open arm in elevated plus maze (EPM). Moreover, CUMS significantly increased the plasma glucose, total cholesterol, triglycerides and total proteins in obese mice. Chronic treatment with QCM-4 (2 mg/kg po) and standard drug escitalopram (10 mg/kg po) significantly reversed the depressive behavioral changes (increased sucrose consumption, decreased immobility time in FST and TST, and increased the percent entries and time in open arm in EPM) and biochemical alterations (reversed the raised levels of plasma glucose, total cholesterol, triglycerides and total proteins) in obese mice subjected to CUMS. No alteration was observed in the locomotor score in obese mice. In conclusion, the results of the present study suggested that QCM-4 attenuated the depression co-morbid with obesity in mice subjected to CUMS which to some extent is mediated by reversing the "insulin resistance" or "altered plasma glucose" in obese mice.

Research paper thumbnail of 5HT3 receptor antagonist (ondansetron) reverses depressive behavior evoked by chronic unpredictable stress in mice: Modulation of hypothalamic–pituitary–adrenocortical and brain serotonergic system

Pharmacology Biochemistry and Behavior, 2014

Chronic stress is one of the major causes of depression, associated with behavioral and biochemic... more Chronic stress is one of the major causes of depression, associated with behavioral and biochemical impairments. 5HT3 receptor antagonists (such as ondansetron) have shown alleviation of depressive symptomology in preclinical and in few clinical studies. However, their effects in chronic stress-induced depressive behavior and the underlying mechanism(s) are yet to be known. In the present study, the effects of a 5HT3 receptor antagonist, ondansetron were evaluated in chronic unpredictable stress (CUS)-evoked depressive behavior. In addition, the possible mechanism was determined by measuring plasma corticosterone (CORT) as a marker of hypothalamic-pituitary-adrenocortical (HPA)-axis activity and serotonin levels in the discrete brain regions. Mice were subjected to a battery of unpredictable stressors for 28 days. Ondansetron (0.05, 0.1 and 1mg/kg, p.o.) and fluoxetine (10mg/kg, p.o.) were administered during the last 14 days (day 15-28th) of CUS testing paradigm. The results showed that the 4-week CUS produced significant depressive behavior in mice, which included increased despair effects in forced swim test (FST) and reward-related deficits in sucrose preference test. Biochemical assays demonstrated a significant increase in percentage of plasma CORT and decrease in percentage of serotonin levels in the discrete brain regions of CUS mice. Chronic ondansetron treatment, similar to that of positive control fluoxetine, significantly reversed despair effects in FST and reward-related deficits in sucrose preference test. In addition, ondansetron and fluoxetine treatments significantly increased percentage of serotonin levels in the measured brain regions and attenuated HPA-axis hyperactivity, as evidenced by low percentage of plasma CORT levels in CUS mice. These findings indicate the potential role of ondansetron (a 5HT3 receptor antagonist) in reversing CUS-induced depressive behavior, which is possibly mediated by its modulating effects on the HPA-axis and serotonergic system. Further, the study represents that 5HT3 receptor antagonists can be a potential therapeutic candidate for stress-related depressive disorders.

Research paper thumbnail of Effect of a novel 5-HT3 receptor antagonist 4i, in corticosterone-induced depression-like behavior and oxidative stress in mice

Steroids, 2015

Stress in our daily life severely affects the normal physiology of the biological system. Dysregu... more Stress in our daily life severely affects the normal physiology of the biological system. Dysregulation of hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the development of depression-like behavior, which remains under diagnosed and poorly treated. Exogenous corticosterone (CORT) administration has been demonstrated to develop a depression model, which has shown to mimic HPA-axis induced depression-like state in rodents. In the present study, the effect of a novel 5HT 3 receptor, 4i was examined on CORT induced depression in mice. CORT (30 mg/kg, subcutaneously) was given for 4-weeks to mice in control group, while mice in drug treated group were given 4i (0.5-1 mg/kg, intraperitoneally)/fluoxetine (as a positive control, 10 mg/kg), for the last 2-weeks of CORT dosing. Repeated CORT dosing caused depression-like behavior in mice as indicated by increased despair effects in forced swim test (FST) and anhedonia in sucrose preference test. In addition, CORT administration induced oxidative load in the brain with significant increase in pro-oxidant (lipid peroxidation and nitrite levels) markers and a substantial decline in anti-oxidant defense (catalase and reduced glutathione levels) system, indicating a direct effect of stress hormones in the induction of the brain oxidative damage. On the other hand, 4i and fluoxetine treatment reversed the CORT induced depressive-like deficits. Furthermore, 4i and fluoxetine prevented CORT induced oxidative brain insults, which may plausibly demonstrate one of the key mechanisms for antidepressant-like effects of the compounds. Thus, the study suggests that 5HT 3 antagonist; 4i may be implicated as pharmacological intervention targeting depressive-like anomaly associated with HPA-axis dysregulation.

Research paper thumbnail of Anxiolytic-like effects of alverine citrate in experimental mouse models of anxiety

European Journal of Pharmacology, 2014

Anxiety disorders are widely spread psychiatric illnesses that are a cause of major concern. Desp... more Anxiety disorders are widely spread psychiatric illnesses that are a cause of major concern. Despite a consistent increase in anxiolytics, the prevalence of anxiety is static; this necessitates the development of new compounds with potential activity and minimum unwanted effects. A serotonergic (5HT) system plays an important role in pathogenesis of anxiety and predominantly involves 5HT 1A receptor action in mediating anxiety-like behavior; the antagonism of 5HT 1A receptor has demonstrated to produce anxiolytic-like effects. Alverine citrate (AVC) is reported as a 5HT 1A antagonist; however, its effects on anxiety-like behavior are not investigated. Thus, the present study, by utilizing a neurobehavioral approach, examined the anxiolytic-like effects of AVC in experimental mouse models of anxiety. Mice were acutely treated with AVC (5-20 mg/kg, i.p.)/diazepam (DIA, 2 mg/kg, i.p.) and subjected to four validated anxiety models viz. elevated plus-maze (EPM), light/dark (L/D), hole-board (HB) and marble burying (MB) tests. AVC (15-20 mg/kg) and DIA significantly increased open arm activity in EPM, exploration in light chamber in L/D test, exploratory behavior in HB and reduced MB behavior in marble burying test. AVC (5 mg/kg) had no effect on all behavioral tests, while AVC (10 mg/kg) produced partial effects. It revealed anxiolytic-like effects of AVC. Furthermore, anxiolytic-like effects of AVC at higher doses (15-20 mg/kg) were more pronounced than lower doses (10 mg/kg) and were quite similar to the standard drug DIA. The present finding demonstrates, for the first time, the anxiolytic-like effects of AVC, which may be an alternative approach for management of anxiety-related disorders.

Research paper thumbnail of Ondansetron attenuates depression co-morbid with obesity in obese mice subjected to chronic unpredictable mild stress; an approach using behavioral battery tests

Metabolic Brain Disease, 2014

Research paper thumbnail of A novel animal model of metabolic syndrome with non-alcoholic fatty liver disease and skin inflammation

Pharmaceutical biology, Jan 28, 2014

Context: Metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) are the emerging co-mor... more Context: Metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) are the emerging co-morbidities of skin inflammation. Occurrence of skin inflammation such as psoriasis is substantially higher in NAFLD patients than normal. Currently, there are no animal models to study the interaction between these co-morbidities. Objective: The present study seeks to develop a simple mouse model of NAFLD-enhanced skin inflammation and to study the effect of NAFLD on different parameters of skin inflammation. Materials and method: Metabolic syndrome and NAFLD were induced in C57BL/6 mice by feeding high-fat diet (HFD, 60% kcal) and high fructose liquid (HFL, 40% kcal) in drinking water. Skin inflammation was induced by repeated application of oxazolone (1% sensitization and repeated 0.5% challenge) in both normal and NAFLD mice and various parameters of skin inflammation and NAFLD were measured. Results: HFD and HFL diet induced obesity, hyperglycemia, hyperinsulinemia, and histological fe...

Research paper thumbnail of Antidepressant-like effects of a novel 5-HT3 receptor antagonist 6z in acute and chronic murine models of depression

Acta pharmacologica Sinica, 2014

To investigate the antidepressant-like effects of a novel 5-HT3 receptor antagonist N-(benzo[d]th... more To investigate the antidepressant-like effects of a novel 5-HT3 receptor antagonist N-(benzo[d]thiazol-2-yl)-3-methoxyquinoxalin-2-carboxamide (6z) in acute and chronic murine models of depression. 5-HT3 receptor antagonism was examined in guinea pig ileum in vitro. A tail suspension test (TST) was used as acute depression model to evaluate the antidepressant-like behavior in mice treated with 6z (0.5-2 mg/kg, ip). In chronic depression model, mice were exposed to a 4-week chronic unpredictable stress (CUS) protocol, and treated with 6z (0.5-2 mg·kg(-1)·d(-1), po) or a positive drug fluoxetine (10 mg·kg(-1)·d(-1), po) in the last 2 weeks, followed by behavioral and biochemical assessments. The 5-HT3 receptor antagonism of 6z (pA2=7.4) in guinea pig ileum was more potent than that of a standard 5-HT3 receptor antagonist ondansetron (pA2=6.9). In acute depression model, 6z administration significantly decreased the immobility duration. In chronic depression model, 6z administration re...

Research paper thumbnail of Antidepressant effects of insulin in streptozotocin induced diabetic mice: Modulation of brain serotonin system

Physiology & Behavior, 2014

• STZ induced diabetes resulted in depression in mice. • STZ induced diabetes exhibited decreased... more • STZ induced diabetes resulted in depression in mice. • STZ induced diabetes exhibited decreased serotonin levels in the brain. • Insulin treatment produced an antidepressant effect in STZ induced diabetic mice. • Insulin significantly increased the brain serotonin concentrations. • Thus, insulin could be acting through modulation of the brain serotonin system.