Novel 5-HT3 receptor antagonist QCM-4 attenuates depressive-like phenotype associated with obesity in high-fat-diet-fed mice
| Autor: | Yeshwant Kurhe, Thangaraj Devadoss, Radhakrishnan Mahesh |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pharmacology Brain-derived neurotrophic factor Elevated plus maze medicine.medical_specialty business.industry Dentate gyrus Insulin medicine.medical_treatment Hippocampal formation medicine.disease Serotonergic 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Insulin resistance Endocrinology chemistry Internal medicine Medicine Cyclic adenosine monophosphate business 030217 neurology & neurosurgery |
| Zdroj: | Psychopharmacology. 234:1165-1179 |
| ISSN: | 1432-2072 0033-3158 |
| DOI: | 10.1007/s00213-017-4558-0 |
| Popis: | 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 5-HT concentrations; and molecular assays mainly histology and immunohistochemistry (IHC) of p53 protein in the dentate gyrus (DG), CA1, and CA3 regions of hippocampus in HFD fed mice were performed. Chronic treatment with QCM-4 in HFD-fed mice reversed the behavioral alterations in SPT, FST, and EPM. QCM-4 showed poor sensitivity for plasma glucose, improved insulin sensitivity, increased hippocampal cAMP, BDNF, and 5-HT concentrations. In the hippocampal DG, CA1, and CA3 regions, QCM-4 treatment improved the neuronal morphology in the histopathology and inhibited p53 protein expression in IHC assay in HFD-fed mice. QCM-4 attenuated the depressive-like phenotype in HFD-fed mice by improving behavioral, biochemical, and molecular alterations through serotonergic neuromodulation. |
| Databáze: | OpenAIRE |
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