Li Xiangzhu, Lu Dongting, Zou Lei, Ma Lijuan, Yang Yukun, Quan Xingyun, Song Wei, Ye Qinlian, Lu Hui-Lun, Brockmeier Ulf, Zhou Yanxia, Huang Guodong, Wang Ya-Chao
Department of Neurosurgery, The Institute Translational Medicine, Shenzhen Second People's Hospital/The First Affiliated Hospital of Shenzhen University, Shenzhen 518035, China.
Shenzhen Traditional Chinese Medicine Hospital, No. 1, Fuhua Road, Futian District, Shenzhen 518033, Guangdong, China.
ACS Omega. 2025 Apr 7;10(15):15461-15470. doi: 10.1021/acsomega.5c00125. eCollection 2025 Apr 22.
Brain ischemia disrupts endoplasmic reticulum (ER) dynamics, causes ER stress, and triggers the unfolded protein response (UPR). During the UPR, protein kinase RNA-like ER kinase (PERK) phosphorylates eIF2α, shutting down global protein synthesis, inhibits protein synthesis, and provides neuroprotection during acute ischemic stroke. Herein, middle cerebral artery occlusion/reperfusion (MCAO/R) and PERK neuron-specific deletion conditional knockout mice were employed to observe the function and mechanisms of PERK. CCT020312, a novel selective PERK activator, specifically activates PERK and provides neuroprotection both in vivo and in vitro stroke models. Additionally, CCT020312 enhanced neuronal survival and cerebral microvessels and decreased the level of astrogliosis in acute ischemic stroke mice. Furthermore, in vivo experiments demonstrated that CCT020312 not only prevented apoptosis but also enhanced the PERK/p-eIF2α/LC3-II autophagy signaling pathway in MCAO/R mice. In conclusion, our study supports the potential therapeutic value of targeting PERK in acute ischemic stroke, offering a promising strategy for enhancing stroke outcomes through the modulation of protein synthesis and the autophagy pathway.
脑缺血会破坏内质网（ER）动态，引发内质网应激，并触发未折叠蛋白反应（UPR）。在UPR过程中，蛋白激酶RNA样内质网激酶（PERK）使真核生物翻译起始因子2α（eIF2α）磷酸化，从而关闭整体蛋白质合成，抑制蛋白质合成，并在急性缺血性卒中期间提供神经保护作用。在此，采用大脑中动脉闭塞/再灌注（MCAO/R）模型和PERK神经元特异性缺失条件性敲除小鼠来观察PERK的功能和机制。CCT020312是一种新型选择性PERK激活剂，在体内和体外卒中模型中均能特异性激活PERK并提供神经保护作用。此外，CCT020312可提高急性缺血性卒中小鼠的神经元存活率和脑微血管数量，并降低星形胶质细胞增生水平。此外，体内实验表明，CCT020312不仅能防止MCAO/R小鼠细胞凋亡，还能增强PERK/p-eIF2α/LC3-II自噬信号通路。总之，我们的研究支持了靶向PERK在急性缺血性卒中治疗中的潜在价值，为通过调节蛋白质合成和自噬途径改善卒中预后提供了一种有前景的策略。
