Methylene blue ameliorates brain edema in rats with experimental ischemic stroke via inhibiting aquaporin 4 expression

• 作者: Zhong-fang Shi Qing Fang Ye Chen Li-xin Xu Min Wu Mei Jia Yi Lu Xiao-xuan Wang Yu-jiao Wang Xu Yan Li-ping Dong Fang Yuan
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（3）
• 所属期刊栏目: Neuropharmacology
• 页码范围: 382-392
• 页数: 11页
• 语种: 英文

摘要

Brain edema is a common and serious complication of ischemic stroke with limited effective treatment.We previously reported that methylene blue(MB)attenuated ischemic brain edema in rats,but the underlying mechanisms remained unknown.Aquaporin 4(AQP4)in astrocytes plays a key role in brain edema.We also found that extracellular signal-regulated kinase 1/2(ERK1/2)activation was involved in the regulation of AQP4 expression in astrocytes.In the present study,we investigated whether AQP4 and ERK1/2 were involved in the protective effect of MB against cerebral edema.Rats were subjected to transient middle cerebral artery occlusion(tMCAO),MB(3 mg/kg,for 30 min)was infused intravenously through the tail vein started immediately after reperfusion and again at 3 h after ischemia(1.5 mg/kg,for 15 min).Brain edema was determined by MRI at 0.5,2.5,and 48 h after tMCAO.The decreases of apparent diffusion coefficient(ADC)values on diffusion-weighted MRI indicated cytotoxic brain edema,whereas the increase of T2 MRI values reflected vasogenic brain edema.We found that MB infusion significantly ameliorated cytotoxic brain edema at 2.5 and 48 h after tMCAO and decreased vasogenic brain edema at 48 h after tMCAO.In addition,MB infusion blocked the AQP4 increases and ERK1/2 activation in the cerebral cortex in ischemic penumbra at 48 h after tMCAO.In a cell swelling model established in cultured rat astrocyte exposed to glutamate(1 mM),we consistently found that MB(10 μM)attenuated cell swelling,AQP4 increases and ERK1/2 activation.Moreover,the ERK1/2 inhibitor U0126(10 μM)had the similar effects as MB.These results demonstrate that MB improves brain edema and astrocyte swelling,which may be mediated by the inhibition of AQP4 expression via ERK1/2 pathway,suggesting that MB may be a potential choice for the treatment of brain edema.