Heliox Preconditioning Exerts Neuroprotective Effects on Neonatal Ischemia/Hypoxia Injury by Inhibiting Necroptosis Induced by Ca2+ Elevation
Heliox Preconditioning Exerts Neuroprotective Effects on Neonatal Ischemia/Hypoxia Injury by Inhibiting Necroptosis Induced by Ca2+ Elevation
复制标题
氦氧预处理通过抑制 Ca2+ 升高引起的坏死性凋亡对新生儿缺血/缺氧损伤发挥神经保护作用
DOI：
10.1007/s12975-022-01021-8
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发表时间：
2022-04-20
影响因子：
6.9
通讯作者：
Li，Yi
中科院分区：
文献类型：
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作者：
Zhong，Weijie;Cheng，Juan;Li，Yi
我们的前期研究表明，heliox预处理（HePC）可能对新生儿缺氧缺血性脑病（HIE）具有神经保护作用。本研究旨在探讨HePC是否通过抑制坏死性上睑下垂来缓解新生儿HIE，并探讨其可能的机制。7日龄大鼠幼崽随机分为Sham组、HIE组、HIE + HePC组、HIE +丹曲林（DAN）组、HIE +坏死他汀-1 （Nec-1）组。通过颈总动脉结扎和随后的缺氧暴露诱导HIE。采用组织学染色、神经行为试验、Western blotting、Ca2+、免疫荧光染色、共免疫沉淀（Co-IP）、透射电镜（TEM）等方法评价大鼠神经功能、脑损伤及分子机制。结果支持HIE后脑内坏死下垂标志物和p-RyR2的表达显著增加。HePC、DAN或Nec-1可改善H/I后的神经功能缺损，抑制神经元坏死。有趣的是，HePC和DAN都抑制了HIE继发的脑细胞质Ca2+和CaMK-II磷酸化的增加，但Nec-1未能影响Ca2+。综上所述，我们的研究结果表明HePC可能通过调节p-RyR2来减轻细胞质Ca2+超载，p-RyR2抑制脑坏死下垂，对HIE发挥神经保护作用。
Our previous studies have indicated that heliox preconditioning (HePC) may exert neuroprotective effects on neonatal hypoxic-ischemic encephalopathy (HIE). The present study was to investigate whether HePC alleviates neonatal HIE by inhibiting necroptosis and explore the potential mechanism. Seven-day-old rat pups were randomly divided into Sham group, HIE group, HIE + HePC group, HIE + Dantrolene (DAN) group, and HIE + Necrostatin-1 (Nec-1) group. HIE was induced by common carotid artery ligation and subsequent hypoxia exposure. The neurological function, brain injury, and molecular mechanism were evaluated by histological staining, neurobehavioral test, Western blotting, Ca2+, immunofluorescence staining, co-immunoprecipitation (Co-IP), and transmission electron microscopy (TEM). Results supported that the expression of necroptosis markers and p-RyR2 in the brain increased significantly after HIE. HePC, DAN, or Nec-1 was found to improve the neurological deficits after H/I and inhibit neuronal necroptosis. Interestingly, both HePC and DAN inhibited the increases in cytoplasmic Ca2+and CaMK-II phosphorylation in the brain secondary to HIE, but Nec-1 failed to affect Ca2+. In conclusion, our results suggest HePC may alleviate cytoplasmic Ca2+overload by regulating p-RyR2, which inhibits the necroptosis in the brain, exerting neuroprotective effects on HIE.