齐墩果酸通过抑制JAK-STAT通路对SAH后早期脑损伤大鼠模型HMGB1表达的影响

Effects of oleanolic acid on the expression of HMGB1 in early brain injury rats after SAH by inhibiting JAK-STAT pathway

目的探究齐墩果酸(OA)通过抑制酪氨酸蛋白激酶(JAK)/信号传导及转录激活因子(STAT)通路对蛛网膜下腔出血(SAH)后早期脑损伤大鼠模型高迁移率族蛋白1(HMGB1)表达的影响。方法雄性Sprague-Dawley级大鼠60只随机分为4组(n=15),即假手术组(sham)、SAH模型组(SAH)、模型+OA组(SAH+OA)以及模型+AG490组(SAH+AG490)。建模1 h后SAH+OA组腹腔注射OA(20 mg/kg),SAH+AG490组在建模前0.5 h腹腔注射AG490(5μmol)。观察建模情况,比较各组大鼠神经功能情况、脑组织含水量、血脑屏障、血清炎性因子[白细胞介素6(IL-6)和肿瘤坏死因子α(TNF-α)]、脑组织JAK-STAT通路和HMGB1蛋白水平。结果SAH组脑组织无实质损伤,但出现显著血块,并出现明显的水肿。SAH组的脑组织含水量和伊文思蓝含量均显著高于sham组(P<0.01),而SAH+OA组和SAH+AG490组的脑组织含水量和伊文思蓝含量显著低于SAH组(P<0.01)。建模后大鼠炎性因子水平显著提高,SAH+OA组和SAH+AG490组的IL-6和TNF-α水平显著低于SAH组(P<0.01)。建模后JAK/STAT和HMGB1蛋白显著上调(P<0.01),SAH+OA组和SAH+AG490组p-JAK、p-STAT和HMGB1蛋白水平显著低于SAH组(P<0.01)。结论OA可能通过抑制JAK/STAT通路下调HMGB1发挥SAH后早期脑损伤保护作用。

Objective To investigate the effects of oleanolic acid(OA)on the expression of high mobility group box 1(HMBG1)in early brain injury rats after subarachnoid hemorrhage(SAH)by inhibiting JAK-STAT pathway.Methods Sixty male Sprague-Dawley rats were randomly divided into 4 groups(n=15),namely sham group,SAH model group(SAH),model+OA group(SAH+OA)and model+AG490 group(SAH+AG490).After 1 hour of modeling,SAH+OA group was intraperitoneally injected with OA(20 mg/kg),and SAH+AG490 group was intraperitoneally injected with AG490(5μmol)0.5 h before modeling.The modeling was observed and the neurological function,brain water content,blood-brain barrier,serum inflammatory factors,brain JAK-STAT pathway and HMGB1 protein levels were compared between the groups.Results The brain tissue of the SAH group had no substantial damage,but there was a significant blood clot and obvious edema.The brain water content and Evans blue content in the SAH group were significantly higher than those in the sham group(P<0.01).The brain water content and Evans blue content in SAH+OA group and SAH+AG490 group were significantly lower than those in SAH group(P<0.01).After modeling,the level of inflammatory factors in rats was significantly increased.The levels of IL-6 and TNF-αin the SAH+OA group and the SAH+AG490 group were significantly lower than those in the SAH group(P<0.01).JAK/STAT and HMGB1 proteins were significantly up-regulated after modeling(P<0.01),the levels of p-JAK,p-STAT and HMGB1 protein in SAH+OA group and SAH+AG490 group were significantly lower than those in SAH group(P<0.01).Conclusion OA may down-regulate HMGB1 by inhibiting JAK/STAT pathway to play a protective role in early brain injury after SAH.