title: Novel 5-HT3receptor antagonist QCM-4 attenuates depressive-like phenotype associated with obesity in high-fat-diet-fed mice.
abstract: 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-HT3receptor 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.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Pilani Campus, Pilani, Rajasthan, 333031, India. yashkurhe@gmail.com.
authors.forename: Yeshwant
authors.initials: Y
authors.lastname: Kurhe
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Pilani Campus, Pilani, Rajasthan, 333031, India.
authors.forename: R
authors.initials: R
authors.lastname: Mahesh
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University (IMU), No. 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia.
authors.forename: Thangaraj
authors.initials: T
authors.lastname: Devadoss
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000523:psychology; D001923:Brain Chemistry / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003863:Depression / Q000150:complications / Q000188:drug therapy* / Q000523:psychology; D059305:Diet, High-Fat; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009765:Obesity / Q000523:psychology*; D011810:Quinoxalines / Q000627:therapeutic use*; D012701:Serotonin / Q000378:metabolism; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000627:therapeutic use*; D013550:Swimming / Q000523:psychology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C000595878:3-methoxy-N-p-tolylquinoxalin-2-carboxamide; D019208:Brain-Derived Neurotrophic Factor; D011810:Quinoxalines; D058831:Serotonin 5-HT3 Receptor Antagonists; D016159:Tumor Suppressor Protein p53; D012701:Serotonin
keywords: BDNF; Depression; Obesity; Serotonin; p53