Faculty of Life Science and Biotechnology, Kunming University of Science and Technology, Kunming, 650500, China; ICU, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, China.
ICU, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, 650500, China.
Eur J Pharmacol. 2021 Jan 15;891:173716. doi: 10.1016/j.ejphar.2020.173716. Epub 2020 Nov 13.
Cerebral damage after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR) is a primary cause of death. Endoplasmic reticulum stress (ERS) is very important during these situations. This study aimed to explore the role of metformin in protecting brain endoplasmic reticulum post CA/CPR. Male SD rats (n = 132) were treated with 6-min CA-posted asphyxia and sham surgery. Before CA/CPR, metformin (200 mg/kg/day) or a vehicle (0.9% saline) were administered randomly for two weeks. The neurological deficit scores were assessed 24 h, 48 h, 72 h, and 7 days after CA/CPR, and the rat brains were analyzed by Western blotting and qRT-PCR. Apoptosis was detected by the TUNEL assay according to the mitochondrial membrane potential (MMP). Oxidative stress and ERS-related protein expression were also investigated. The Western blotting and qRT-PCR results revealed that the resuscitated animals had time-dependent elevated GRP78 and XBP1 levels compared with the sham operative rats. Moreover, our results showed that the rats treated with metformin had increased neurological deficit scores (NDS), an improved seven-day survival rate, decreased cell apoptosis within the hippocampus CA1 area, and less oxidative stress compared with the CA/CPR group. Furthermore, metformin inhibited the mRNA and protein expressions of glucose-regulated protein 78 (GRP78) and X-box binding protein 1 (XBP1) in the CA/CPR rat model. We confirmed that CA/CPR can induce ERS-related apoptosis and oxidative stress in the brain; moreover, inhibiting ERS-related proteins GRP78 and XBP1 with metformin might attenuate cerebral injury post CA/CPR.
心脏骤停（CA）和心肺复苏（CPR）后的脑损伤是死亡的主要原因。内质网应激（ERS）在这些情况下非常重要。本研究旨在探讨二甲双胍在保护 CA/CPR 后大脑内质网中的作用。雄性 SD 大鼠（n=132）接受 6 分钟 CA 后窒息和假手术处理。在 CA/CPR 之前，随机给予二甲双胍（200mg/kg/天）或载体（0.9%生理盐水）治疗两周。CA/CPR 后 24、48、72 小时和 7 天评估神经功能缺损评分，并通过 Western blot 和 qRT-PCR 分析大鼠大脑。根据线粒体膜电位（MMP）检测细胞凋亡采用 TUNEL 检测法。还研究了氧化应激和 ERS 相关蛋白的表达。Western blot 和 qRT-PCR 结果显示，与假手术组大鼠相比，复苏动物的 GRP78 和 XBP1 水平随时间呈依赖性升高。此外，与 CA/CPR 组相比，用二甲双胍治疗的大鼠具有更高的神经功能缺损评分（NDS）、提高的 7 天存活率、海马 CA1 区细胞凋亡减少和更少的氧化应激。此外，二甲双胍抑制 CA/CPR 大鼠模型中葡萄糖调节蛋白 78（GRP78）和 X 盒结合蛋白 1（XBP1）的 mRNA 和蛋白表达。我们证实 CA/CPR 可诱导大脑中 ERS 相关的细胞凋亡和氧化应激；此外，用二甲双胍抑制 ERS 相关蛋白 GRP78 和 XBP1 可能减轻 CA/CPR 后的脑损伤。
