富马酸二甲酯对大鼠脑缺血再灌注损伤的影响

Effects of dimethyl fumarate on cerebral I/R injury in rats

目的研究富马酸二甲酯(DMF)对大鼠脑缺血再灌注损伤的影响及其机制。方法 80只SD大鼠随机分为假手术(Sham)组、手术组、溶剂对照(DMSO)组和DMF组,每组20只,制备短暂性大脑中动脉阻塞(tMCAO)模型,并记录术前和造模后1、3、7 d的神经功能评分。观察大鼠术后脑梗死体积、脑含水量和病理结构改变;各组大鼠缺血半暗带区取材,Western blot测各组核转录因子E2相关因子2(Nrf2)、血红素加氧酶1(HO-1)、醌氧化还原酶1(NQO1)、谷胱甘肽转移酶1(GSTα-1)、胶质原纤维酸性蛋白(GFAP)、水通道蛋白4(AQP4)、离子钙结合衔接分子1(Iba1)蛋白表达。结果 DMF组较手术组和DMSO组术后1、3、7 d Longa评分明显降低(P<0.01);且DMF组大鼠较手术组和DMSO组脑梗死体积和脑含水量明显减少(P<0.05)。DMF组较DMSO组大鼠缺血半暗带区细胞水肿、核固缩边缘化、成空泡状排列等病理改变减少,且术后7 d DMF组大鼠Nrf2(1.08±0.26 vs 0.79±0.21)、HO-1(1.09±0.42 vs 0.62±0.22)、NQO1(1.37±0.32 vs 0.58±0.35)、GSTα-1(1.12±0.09 vs 0.50±0.28)蛋白表达明显增高,而GFAP、Iba1和AQP4蛋白表达明显降低(P<0.05,P<0.01)。结论 DMF可改善tMCAO模型的神经功能及预后,其机制可能与DMF减轻神经细胞Nrf2介导氧化应激和抑制胶质增生相关。

Objective To study the effect of dimethyl fumarate(DMF) on cerebral I/R injury in rats and its mechanism.Methods Eighty adult male SD rats were randomly divided into sham operation group, model group, DMSO group and DMF group(20 in each group).The tMCAO model of rats was established by modified Longa occlusion.The neurological function score was recorded before operation and on days 1,3,7 after modeling.The cerebral infarction size and water content were measured.The change of pathological structure was observed.The expressions of NrF2,HO-1,NQO1,GSTα-1,GFAP,AQP4,and Iba1 in different groups were detected by Western blot.Results The Longa score was significantly lower in DMF group than in sham operation group on days 1,3,7 after operation(P<0.01).The cerebral infarction size was significantly smaller and the cerebral water content was significantly lower in DMF group than in sham operation group and DMSO group(P<0.05).The pathological change of cell edema, nuclear pyknosis marginalization, and vacuolar arrangement was significantly milder in DMF group than in DMSO group.The expression levels of Nrf2,HO-1,NQO1 and GSTα-1 proteins were significantly higher in DMF group on day 7 after operation than before operation(1.08±0.26 vs 0.79±0.21,1.09±0.42 vs 0.62±0.22,1.37±0.32 vs 0.58±0.35,1.12±0.09 vs 0.50±0.28) while those of GFAP,Iba1 and AQP4 proteins were significantly lower in DMF group on day 7 after operation than before operation(P<0.05,P<0.01).Conclusion DMF can improve the neurological function and outcome of tMCAO model by reducing the Nrf2-mediated oxidative stress and inhibiting the proliferation of reactive gliosis.