Department of Anesthesiology, Shengjing Hospital, China Medical University, Shenyang, 110004, People's Republic of China.
Neurochem Res. 2019 Feb;44(2):347-356. doi: 10.1007/s11064-018-2682-9. Epub 2018 Nov 20.
Hypoxic-ischemic brain injury (HIBI) in neonates is one of the major contributors of newborn death and cognitive impairment. Numerous animal studies have demonstrated that autophagy is substantially increased in HIBI and that sevoflurane postconditioning (SPC) can attenuate HIBI. However, if SPC-induced neuroprotection inhibits autophagy in HIBI remains unknown. To investigate if cerebral protection induced by SPC is related to decreased autophagy in the setting of HIBI. Postnatal rats at day 7 (P7) were randomly assigned to 7 different groups: Sham, HIBI, SPC-HIBI, HIBI + rapamycin, SPC-HIBI + rapamycin, HIBI + p-extracellular signal-regulated kinase (p-ERK) inhibitor, and SPC-HIBI + p-ERK inhibitor. To induce HIBI, neonatal rats underwent left common carotid artery ligation, followed by 2 h of hypoxia (8% O). Rats in the SPC groups were treated with 1 minimum alveolar concentration ([MAC], 2.4%) SPC for 30 min after HIBI induction. Markers of autophagy and expression of ERK cascade components were measured in the rat brains after 24 h. Spatial learning and memory function were examined 29-34 days after administration of an autophagy agonist or a p-ERK inhibitor. The expression of microtubule-associated proteins 1A/1B, light chain 3B II (LC3-II) and tuberous sclerosis complex 2 (TSC2) were decreased in the SPC-HIBI group compared to the HIBI group. Expression of the p62 sequestosome 1 (P62/SQSTM1) protein, p-ERK/ERK, phospho-mammalian target of rapamycin (p-mTOR) and phospho-p70S6 were increased in SPC-HIBI group. Rats within the SPC-HIBI groups that also received the p-ERK inhibitor or autophagy inhibitor demonstrated reduced cross platform times and increased escape latency. Approximately 30 min of 2.4% SPC treatment in the P7 rat HIBI model attenuated excessive autophagy in the brain by elevating the ERK cascade. This finding provides additional insight into HIBI and identifies new targets for therapeutic approaches to treat HIBI.
新生儿缺氧缺血性脑损伤（HIBI）是新生儿死亡和认知障碍的主要原因之一。大量动物研究表明，自噬在 HIBI 中显著增加，七氟醚后处理（SPC）可以减轻 HIBI。然而，SPC 诱导的神经保护是否抑制 HIBI 中的自噬尚不清楚。本研究旨在探讨 SPC 诱导的脑保护是否与 HIBI 中自噬的减少有关。生后 7 天（P7）的大鼠被随机分为 7 组：假手术组、HIBI 组、SPC-HIBI 组、HIBI+雷帕霉素组、SPC-HIBI+雷帕霉素组、HIBI+p-细胞外信号调节激酶（p-ERK）抑制剂组和 SPC-HIBI+p-ERK 抑制剂组。通过结扎左侧颈总动脉并缺氧（8% O2）2 h 诱导 HIBI。SPC 组大鼠在 HIBI 诱导后给予 1 个最低肺泡浓度（[MAC]，2.4%）SPC 处理 30 min。在 HIBI 后 24 h 测量大鼠脑组织中的自噬标志物和 ERK 级联成分的表达。在给予自噬激动剂或 p-ERK 抑制剂后 29-34 天，检测空间学习和记忆功能。与 HIBI 组相比，SPC-HIBI 组大鼠脑中微管相关蛋白 1A/1B、微管相关蛋白 1A/1B、轻链 3B II（LC3-II）和结节性硬化复合物 2（TSC2）的表达减少，而 p62 自噬体相关蛋白 1（P62/SQSTM1）蛋白、p-ERK/ERK、磷酸化哺乳动物雷帕霉素靶蛋白（p-mTOR）和磷酸化 p70S6 的表达增加。SPC-HIBI 组大鼠接受 p-ERK 抑制剂或自噬抑制剂后，穿越平台的次数减少，逃避潜伏期延长。在 P7 大鼠 HIBI 模型中，约 30 min 的 2.4% SPC 处理通过升高 ERK 级联来减轻大脑中的过度自噬。这一发现为 HIBI 提供了新的认识，并确定了治疗 HIBI 的新靶点。
