| Depression is the most debilitating neuropsychiatric disorder with significant impacts on the socio-occupational and well-being of the individual,and chronic stresses,especially psychosocial stressors,are well-known risk factors for the onset of depression.Although the mechanism of the onset of depression is not clear yet,many studies reported that depression is closely associated with chronic inflammation in the brain.Microglia are the resident immune cells in the central nervous system(CNS)and are the principal mediators of inflammation in CNS.Cycloxygenase-2(COX-2)is a key enzyme in inflammatory responses and its expression significantly increases upon stimulation by inflammatory cytokines.Mefenamic acid(MA)is one of the nonsteroidal anti-inflammatory drugs(NSAIDs)and is a competitive inhibitor of COX.MA exerts anti-inflammatory,analgesic,and antipyretic effects.In this study,we investigated the neuroprotective potential of MA with anti-inflammatory properties for the depression induced by chronic stress.MA could inhibit the activation of microglia induced by endotoxin LPS in cellular assay with BV2 microglia,shown by the inhibition of ERK1/2 and P38 MAPK activation and significant reduction of the expression of inducible Nitric Oxide Synthase(i NOS).Immunohistochemistry studies showed that,compared to the stressed mice,the number of activated and phagocytic microglia(Iba1+and CD68+)in Dentate gyrus(DG)of hippocampus significantly decreases in stressed mice treated with MA(5mg/kg).Behavioral assays for depressive behaviors such as sucrose preference test and forced swimming test revealed that MA could ameliorate the anhedonia behavior and lack of survival caused by chronic stress.MA also reduced high phagocytic activity of LPS-treated microglia.These results suggest that MA can reduce neuroinflammation by the inhibition of microglia activation/phagocytosis upon chronic stress,resulting in the improvement of depressive symptoms. |
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