Protective effects of a novel 5-HT_3 receptor antagonist, N-n-butyl-3-methoxy quinoxaline-2-carboxamide (60) against chronic unpredictable mild stress-induced behavioral changes and biochemical alterations

摘要

Stimulation of high oxidative stress in the brain is considered as an important factor for neurotoxicity towards the pathophysiology of chronic stress-induced depression disorder. In the present research, a potential 5-HT_3 receptor antagonist N-n-butyl-3-methoxy quinoxaline-2-carboxamide (60) having good Log P (2.60) and pA_2 (7.7) values was examined for its effect on the behavioral and biochemical changes induced by the chronic unpredictable mild stress (CUMS) model. In the current investigation mice were introduced to different stress procedures daily for a period of 28 days to induce a depressive-like behavior. The results show that CUMS caused a depression-like behavior in mice, as indicated by the significant decrease in sucrose consumption and locomo-tor activity and increase in immobility in the forced swim test (FST). Moreover, it was found that oxidative stress markers such as lipid peroxide and nitrite levels were significantly increased, whereas, antioxidant enzymes such as glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels were decreased in the brain tissue of CUMS-subjected mice. "Compound 60" (1 and 2 mg/kg, p.o.) and fluoxetine treatment (20 mg/kg, p.o.) for a period of 21 days altered the CUMS-induced behavioral (increased immobility period, reduced sucrose preference and decreased locomotor activity) and biochemical (increased lipid peroxide, increased brain nitrite; decreased GSH, SOD and CAT levels) alterations. Moreover normal mice treated with "compound 60" (2 mg/kg, p.o.) showed a significant decrease in the duration of immobility in FST as compared to normal vehicle treated mice. In conclusion, "compound 60" produced antidepressant-like effects in behavioral despair paradigm in chronically stressed mice by restoring antioxidant enzyme activity.