Anti-Depressant-Like Effect of Vemurafenib in Chronic Unpredictable Mild Stress-Induced Depression Using Animal Model

The present study aimed to investigate whether vemurafenib has an anti-depressant-like effect in a rat model of depression induced by chronic unpredictable mild stress (CUMS), and to explore the underlying mechanisms. Male albino rats were subjected to the CUMS for 6 weeks with unpredictable stressors to induce depression and the vemurafenib treatment was started at the 22 nd day i.e. 4th week (for 21 days during 6 weeks of the protocol). CUMS significantly increased immobility period in the forced swimming test and decrease consumption of sucrose in the sucrose preference test in rats. Furthermore, a significant reduction in the brain-derived neurotrophic factor (BDNF) levels and increased phosphorylated NF-kappa B levels (p-NF-kappa B) was observed in the prefrontal cortex brain region. However, vemurafenib (30 and 50 mg/kg) significantly reversed sucrose consumption as well as reduced immobility times in CUMS-subjected rats in a dose-dependent manner, suggesting the antidepressant potential of vemurafenib. Moreover, vemurafenib significantly increased BDNF expression and decreased p-NF-kappa B expressions in the prefrontal cortex (PFC) of the brain of stress-subjected rats. Co-administration of ANA-12, tropomyosin receptor kinase B (TrkB) antagonist (0.25 and 0.5 mg/kg) with vemurafenib (50 mg/kg) considerably attenuated vemurafenib-mediated antidepressant effects of sucrose preference behavior and immobility period in CUMS subjected rats. ANA-12 abolished a vemurafenib-mediated decrease in the p-NF-xB and an increase in BDNF levels in stress-subjected. The antidepressant actions of vemurafenib may be attributed to an increase in the expression of BDNF and a decrease in the expression of p-NF-kappa B in the stress-sensitive PFC region of the brain. Vemurafenib-mediated modulation of BDNF/NF-kappa B signaling may contribute to attenuating depressive-symptoms in CUMS-subjected rats.