Pharmacological Profiling of Mefenamic Acid Derivative (2-((2,3-dimethylphenyl)amino)phenyl)(4-ethylpiperazin-1-yl)methone) for its Antidepressant- and Anxiolytic-like Potential Using Corticosterone Induced Depression Model in Rodents.

Recent studies demonstrated that serotonergic system, specially 5-HT3 receptor (5-HT3R) plays major role in regulating mood and anxiety. The present study investigates antidepressant- and anxiolytic-like effects of a 5-HT3 receptor antagonist (5-HT3RA), (2-((2,3-dimethylphenyl)amino)phenyl)(4- ethylpiperazin-1-yl)methone) (MP-02), in mouse model of corticosterone-induced depression. Chronic administration of corticosterone (CORT) was done to induce depression- and anxiety-like behaviour in mice. It mimics stress-related pathophysiology due to involvement of HPA axis. Behavioural evaluations, such as spontaneous locomotor activity (SLA), forced swim test (FST), tail suspension test (TST), open field test (OFT), elevated plus maze (EPM), light and dark (L&D) test, sucrose preference test (SPT), were performed to assess antidepressant-and anxiolytic-like effects. Biochemical evaluations such as plasma CORT and serotonin, brain inflammatory marker and oxidative stress marker levels were measured in mouse brain. Administration of MP-02 led to significant reduction in immobility time during the FST and TST and increased % sucrose preference in SPT, which reflects antidepressant-like effect and it enhances the exploratory behaviour in OFT, EPM and L&D test which indicates anxiolytic-like effects. It also decreases the levels of plasma CORT and brain inflammatory markers TNF-α, IL-1β and oxidative stress marker, MDA and increases the levels of brain serotonin and anti-oxidant enzyme catalase and SOD. However, MP-02 was not affected the levels of BDNF in mouse brain. The present study demonstrated the potential antidepressant and anxiolytic-like effects of MP-02 in mice. The results were further supported by docking simulations, offering molecular insights into the understanding of the experimental results.