目的 基于 PERK/eIF2α/ATF4/CHOP 信号通路探讨四味黄芪散 （藏黄芪、藏红花、川芎、沉香） 对高原低氧致脑损伤大鼠的保护作用及机制。方法 将 SD 大鼠随机分为空白组、模型组、阳性药物组 （诺迪康，0.125 g•kg-1•d-1） 以及四味黄芪散低、中、高剂量组 （3.255、6.510、13.020 g•kg-1•d-1） ，每组 10 只。四味黄芪散各剂量组灌胃给药，每日 1 次，连续 14 d；阳性药物组给予诺迪康灌胃给药，每日 1 次，连续给药 7 d。采用实验动物低压模拟舱复制高原低氧致脑损伤大鼠模型，低氧暴露持续 7 d。采用 HE 染色法观察大鼠脑组织病理变化；TUNEL 染色法检测大鼠脑组织细胞凋亡情况；TBA 法、微板法分别检测脑组织中丙二醛 （MDA） 、谷胱甘肽 （GSH） 的水平；Western Blot 法检测大鼠脑组织中 p-PERK/PERK、p-eIF2α/eIF2α、ATF4、CHOP 蛋白表达水平；RT-qPCR 法检测大鼠脑组织中 PERK、eIF2α、ATF4、CHOP mRNA 表达水平。结果 与空白组比较，模型组大鼠海马 CA1 区锥体细胞水肿，排列不规则，胞质疏松淡染；海马 CA1 区红色荧光强度显著增强（P＜0.01）；脑组织中 MDA 含量显著升高（P＜0.01），GSH 活性显著降低（P＜0.01）；脑组织中 p-PERK/PERK、p-eIF2α/eIF2α、ATF4、CHOP 蛋白表达水平显著升高 （P＜0.01） ，PERK、eIF2α、ATF4、CHOP mRNA表达显著上调 （P＜0.01） 。与模型组比较，阳性药物组及四味黄芪散高、中、低剂量组大鼠海马 CA1 区锥体细胞排列紧密，边界较清，细胞水肿得到改善；海马 CA1 区的红色荧光强度明显减弱 （P＜0.05） ；脑组织中 MDA含量显著降低 （P＜0.01） ，GSH 活性显著升高 （P＜0.05，P＜0.01） 。四味黄芪散高、中剂量组大鼠脑组织中p-PERK/PERK、p-eIF2α/eIF2α、ATF4、CHOP 蛋白表达水平显著降低 （P＜0.05，P＜0.01） ，PERK、eIF2α、ATF4、CHOP mRNA 表达显著下调 （P＜0.05，P＜0.01） ；四味黄芪散低剂量组大鼠脑组织中 p-eIF2α/eIF2α、CHOP 蛋白表达水平显著降低 （P＜0.05，P＜0.01） ，eIF2α、CHOP mRNA 表达显著下调 （P＜0.05，P＜0.01） 。结论 四味黄芪散能改善高原低氧致脑损伤大鼠的脑组织神经元细胞水肿，增强抗氧化应激能力，减少脑组织细胞凋亡，可能与其调控 PERK/eIF2α/ATF4/CHOP 信号通路抑制内质网应激有关。

Objective To investigate the protective effect of Siwei Huangqi Powder （Astragalus tibeticola Podlech，Croci Stigma，Chuangxiong Rhizoma，Aquilariae Lignum Resinatum） on rats with high-altitude hypoxia-induced brain injury based on the protein kinase R-like endoplasmic reticulum kinase（PERK）/eukaryotic translation initiation factor 2α （eIF2α）/transcription activator 4 （ATF4）/endoplasmic reticulum stress enhancer binding （C/EBP）homologous protein （CHOP） signaling pathway. Methods SD rats were randomly divided into blank group，model group，the high-，medium- and low- dose of Siwei Huangqi Powder groups（3.255，6.510，13.020 g•kg-1•d-1）and positive drug group （Nuodikang，0.125 g•kg-1•d-1），with 10 rats in each group. Each dose group of Siwei Huangqi Powder was administered by gavage，once a day for 14 days. The rats in the positive drug group were given Nuodikang by gavage，once a day for seven days. A rat model of plateau hypoxic brain injury was replicated in a low-pressure simulation chamber，hypoxic exposure for seven days. HE staining was used to observe pathological changes in rat brain tissue. TdT-mediated dUTP nick end- labeling（TUNEL）staining was used to detect the apoptosis of brain cells. The contents of malondialdehyde （MDA） and glutathione （GSH） in brain tissue were detected by TBA and microplate method，respectively. The protein expressions of p-PERK/PERK，p-eIF2α/eIF2α，ATF4 and CHOP in brain tissue were detected by Western Blot. RT-qPCR was used to detect the mRNA expression of PERK，eIF2α，ATF4 and CHOP in rat brain tissue. Results Compared with the blank group，the pyramidal cells in the hippocampal CA1 region of the model group were edema，irregularly arranged，and the cytoplasm was loose and lightly stained. The intensity of red fluorescence in hippocampal CA1 region was significantly increased （P＜0.01）. The content of MDA in brain tissue was significantly increased （P＜0.01），and the activity of GSH was significantly decreased （P＜0.01）. The protein expression levels of p-PERK/PERK，p-eIF2α/eIF2α，ATF4 and CHOP in brain tissue were significantly increased（P＜0.01）. The mRNA expression levels of PERK，eIF2α，ATF4 and CHOP in brain tissue were significantly up-regulated（P＜0.01）. Compared with the model group，the pyramidal cells in the hippocampal CA1 region of the rats in positive drug group and Siwei Huangqi Powder groups were closely arranged，the boundary was clear，and the cell edema was improved. The intensity of red fluorescence in hippocampal CA1 region was significantly decreased （P＜0.05）. The content of MDA in brain tissue was significantly decreased （P＜0.01），and the activity of GSH was significantly increased （P＜0.05，P＜0.01）. The protein expressions of p-PERK/PERK，p-eIF2α/eIF2α，ATF4 and CHOP in the brain tissue of the high- and medium- dose of Siwei Huangqi Powder groups were significantly decreased （P＜0.05，P＜0.01），while the mRNA expression levels of PERK，eIF2α，ATF4 and CHOP were significantly down-regulated（P＜0.05，P＜0.01）. The protein expressions of p-eIF2α/eIF2α and CHOP in the brain tissue of the low-dose Siwei Huangqi Powder group were significantly decreased （P＜0.05，P＜0.01），while the mRNA expression levels of eIF2α and CHOP were significantly down-regulated （P＜0.05，P＜0.01）. Conclusions Siwei Huangqi Powder can reduce the edema of neuronal cells in brain tissue，increase the ability of anti-oxidative stress， and reduce the apoptosis of brain neuronal cells in rats with high-altitude hypoxia-induced brain injury，possibly by regulating the PERK/eIF2α/ATF4/CHOP signaling pathway to inhibit endoplasmic reticulum stress.

R285.5

甘肃省高等学校青年博士基金项目（2022QB-102）；甘肃中医药大学引进人才科研启动基金项目 （2023YJRC-06）；甘肃中医药大学研究生创新创业项目