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

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Abstract

Rationale

Depression associated with obesity remains an interesting area to study the biological mechanisms and novel therapeutic intervention.

Objectives

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.

Methods

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.

Results

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.

Conclusion

QCM-4 attenuated the depressive-like phenotype in HFD-fed mice by improving behavioral, biochemical, and molecular alterations through serotonergic neuromodulation.

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Acknowledgments

The authors are thankful to Birla Institute of Technology and Science (BITS), Pilani, India, for providing the support and research facilities to pursue this work.

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Authors and Affiliations

  1. Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Pilani Campus, Pilani, Rajasthan, 333031, India

    Yeshwant Kurhe & R. Mahesh

  2. Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University (IMU), No. 126, Jalan Jalil Perkasa 19, 57000, Bukit Jalil, Kuala Lumpur, Malaysia

    Thangaraj Devadoss

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  1. Yeshwant Kurhe
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Correspondence to Yeshwant Kurhe.

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Kurhe, Y., Mahesh, R. & Devadoss, T. Novel 5-HT3 receptor antagonist QCM-4 attenuates depressive-like phenotype associated with obesity in high-fat-diet-fed mice. Psychopharmacology 234, 1165–1179 (2017). https://doi.org/10.1007/s00213-017-4558-0

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