Mefenamic acid can attenuate depressive symptoms by suppressing microglia activation induced upon chronic stress

Background: Depression is the most debilitating neuropsychiatric disorder, and psychosocial stressors are major risk factors for the onset of depression. Depression is closely associated with chronic inflammation and microglia are the principal mediators of inflammation in the central nervous system (CNS). Mefenamic acid (MA) and celecoxib are nonselective and selective inhibitors of cyclooxygenase (COX), respectively. COX is a key enzyme in mediating inflammatory response in microglia. In this study, we examine the effects of inhibiting COX by MA on depressive-like behaviors and microglia activation in the hippocampus. Methods: We evaluate the effect of MA on chronic mild stress (CMS) induced depressive-like behavior by sucrose preference and forced swimming tests. Effect of MA on microglia activation in dentate gyrus (DG) of hippocampus was examined by immunohistochemistry. In vitro experiments including western blotting and phagocytosis assay were used to investigate the effect of MA on microglia activation. Results: Behavioral assays reveal MA and celecoxib ameliorate CMS-induced depressive-like behavior. Compared to the stressed mice, the number of activated/phagocytic microglia (Iba1(+)/CD68(+)) in DG of hippocampus significantly decreases in stressed mice treated with MA or celecoxib. MA and celecoxib play a role in inhibiting microglia activation by inhibiting of ERK1/2 and P38 MAPK activation and iNOS expression. MA or celecoxib also reduce the high phagocytic activity of activated microglia. Conclusion: MA inhibits microglia activation/phagocytosis induced upon chronic stress in the hippocampus, which might result in the improvement of depressive symptoms.