Edaravone attenuates brain edema and injury by down-regulating expressions of p38 mitogen-activated protein kinase and aquaporin-4 after focal cerebral ischemia and reperfusion in mice

Abstract

Objective To investigate the effects on brain tissue p38 mitogen-activated protein kinase (MAPK) and aquaporin 4 (AQP4) and neuroprotective effect of edarvone after focal cerebral ischemia and reperfusion in mice. Methods A total of 196 healthy male Kunming mice were randomly divided into four groups: a sham operation group, an ischemia-reperfusion group, a saline control group, and an edaravone group (n=49 in each group). A middle cerebral artery occlusion (MCAO) mothod was used to induce a cerebral ischemia-reperfusion model. At 2 h after ischemia, immediately after reperfusion in the edaravone group and the saline control group, edaravone (5 mg/kg) and the same volume of saline were injected intraperitoneally in mice, then repeated once every 24 h. At 2 h after MCAO, the brain water content and infarct volume at different time points after reperfusion (12 h, 24 h, 48 h, and 3 d) were measured respectively. At 24 h after MCAO, the expressions of AQP4 and p38 MAPK in the brain tissue of ischemic peripheral cortex were measured by Western blotting. Results The volumes of cerebral infarction (all P<0.01) and the brain water contents (all P<0.05) in the edaravone group were decreased than those in the ischemia-reperfusion group and saline control group at different time points, and they were most significant at 48 h. After 24-h reperfusion, the expression levels of AQP4 (0.985±0.129, 1.024±0.117, 0.713±0.231) and phospho-p38 MAPK (1.123±0.142, 1.214±0.096, 0.986±0.087) in the brain tissue of ischemic peripheral cortex in the ischemia-reperfusion group, the saline control group, and the edaravone group were upregulated significantly than those in the sham operation group (AQP4: 0.265±0.123; phospho-p38 MAPK: 0.465±0.023; all P<0.01), but edaravone group were significantly lower than the ischemia-reperfusion group and the saline control group (all P<0.05). Conclusions Edaravone can downregulate the expression level of AQP4 and effectively protect cerebral ischemia reperfusion injury in mice, Its mechanism may be associated with the inhibition of p38 MAPK pathway. Key words: Brain Ischemia; Reperfusion Injury; Brain Edema; Cerebral Infarction; Aquaporin 4; p38 Mitogen-Activated Protein Kinases; Neuroprotective Agents; Mice; Edaravone