title: Effect of a novel 5-HT3 receptor antagonist 4i, in corticosterone-induced depression-like behavior and oxidative stress in mice.
abstract: 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 5HT3 receptor, 4i was examined on CORT induced depression in mice. CORT (30mg/kg, subcutaneously) was given for 4-weeks to mice in control group, while mice in drug treated group were given 4i (0.5-1mg/kg, intraperitoneally)/fluoxetine (as a positive control, 10mg/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 5HT3 antagonist; 4i may be implicated as pharmacological intervention targeting depressive-like anomaly associated with HPA-axis dysregulation.
authors: Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan 333031, India. Electronic address: deepaligupta2010@gmail.com.
authors: Deepali
authors: D
authors: Gupta
authors: Faculty Affairs and Professor, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Rajasthan 333031, India. Electronic address: rmaheshbits@gmail.com.
authors: Mahesh
authors: M
authors: Radhakrishnan
authors: Department of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan 333031, India. Electronic address: yashkurhe@gmail.com.
authors: Yeshwant
authors: Y
authors: Kurhe
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002374:Catalase / Q000378:metabolism; D003345:Corticosterone / Q000009:adverse effects*; D003863:Depression / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009573:Nitrites / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011810:Quinoxalines / Q000494:pharmacology* / Q000627:therapeutic use; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D013550:Swimming
chemical_list: C000594644:N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide; D009573:Nitrites; D011810:Quinoxalines; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D002374:Catalase; D005978:Glutathione; D003345:Corticosterone
keywords: 5HT(3) receptor antagonist; Corticosterone; Depression; HPA-axis; Oxidative stress