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Updated: Dec 23, 2025
The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice
Published on: October 24, 2018
Mefenamic acid can attenuate depressive symptoms by suppressing microglia activation induced upon chronic stress
Xiaoye Feng1, Yang Fan1, Chang Y Chung2
1School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
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.
Insights
Mefenamic acid (MA) reduces depression-like behaviors and microglia activation in the hippocampus. This non-selective cyclooxygenase (COX) inhibitor may improve depressive symptoms by calming neuroinflammation.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Depression is a major neuropsychiatric disorder linked to chronic inflammation.
- Microglia are key mediators of central nervous system (CNS) inflammation.
- Cyclooxygenase (COX) enzymes are involved in microglial inflammatory responses.
Purpose of the Study:
- To investigate the effects of mefenamic acid (MA), a COX inhibitor, on depressive behaviors.
- To examine MA's impact on microglia activation in the hippocampus.
- To understand the role of COX inhibition in neuroinflammation and depression.
Main Methods:
- Evaluated MA's effect on chronic mild stress (CMS)-induced depressive behaviors using sucrose preference and forced swimming tests.
- Assessed microglia activation in the hippocampus via immunohistochemistry.
- Utilized in vitro western blotting and phagocytosis assays to study MA's effects on microglia.
Main Results:
- Both MA and celecoxib (a selective COX inhibitor) alleviated CMS-induced depressive behaviors.
- MA and celecoxib significantly reduced the number of activated microglia (Iba1+/CD68+) in the hippocampus.
- MA and celecoxib inhibited microglia activation by suppressing ERK1/2 and P38 MAPK pathways and iNOS expression, reducing microglial phagocytosis.
Conclusions:
- Mefenamic acid (MA) effectively inhibits stress-induced microglia activation and phagocytosis in the hippocampus.
- MA's anti-inflammatory actions on microglia may contribute to the improvement of depressive symptoms.
- Targeting COX-mediated inflammation in microglia presents a potential therapeutic strategy for depression.
