Department of Neurology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China; Guangxi Key Laboratory of Chinese Medicine Foundation Research, Guangxi University of Chinese Medicine, Nanning, Guangxi, China.
Department of Neurology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi, China; Graduate College of Guangxi University of Traditional Chinese Medicine, Nanning, Guangxi, China.
Brain Res. 2021 Feb 1;1752:147216. doi: 10.1016/j.brainres.2020.147216. Epub 2020 Dec 14.
Cerebral ischemia is the most common cause of hippocampal neuronal death and the most prevalent cause of stroke with high mortality rate. Ferroptosis has been suggested to affect the role of hippocampal neurons. This study explores the influence of lentivirus infection-induced ferritin overexpression in hippocampal neuronal injury and death through simulations in August Copenhagen Irish rat models. Twenty-four-hour cerebral ischemia-reperfusion injury was induced in the rats after 90-min middle cerebral artery occlusion (MCAO). Ferritin overexpression was induced through lentivirus infection. The Morris Water Maze (MWM) test and tau hyperphosphorylation test were performed on hippocampal neurons to establish a MCAO model. The effect of ferritin overexpression on hippocampal neuronal death was evaluated using hematoxylin-eosin staining and annexin V/propidium iodide flow cytometry. The MWM test revealed that MCAO modeling decreased the cognitive and locomotor capacity of the rats, whereas ferritin overexpression partially reversed the effect of MCAO. In addition, the hyperphosphorylation of tau caused by MCAO was reduced by ferritin. Pathogenic changes, impaired viability, increased apoptosis, and elevated caspase-9 cleavage in hippocampal neurons were clearly recovered by ferritin. Moreover, robust reactive oxygen species production and glutathione consumption, which was induced by MCAO modeling, were ameliorated by ferritin. Furthermore, two key modulators of ferroptosis, p53 and SLC7A11, were demonstrated to be upregulated by MCAO modeling and downregulated by ferritin. Ferritin reduction is essential for cerebral ischemia-induced hippocampal neuronal ferroptosis mediated via p53 and SLC7A11.
脑缺血是海马神经元死亡的最常见原因，也是卒中的最常见原因，其死亡率较高。铁死亡被认为会影响海马神经元的功能。本研究通过 August Copenhagen Irish 大鼠模型模拟，探讨了感染性慢病毒诱导铁蛋白过表达对海马神经元损伤和死亡的影响。在大脑中动脉闭塞（MCAO） 90 分钟后，通过慢病毒感染诱导铁蛋白过表达，诱导大鼠发生 24 小时脑缺血再灌注损伤。采用 Morris 水迷宫（MWM）试验和 tau 过度磷酸化试验建立 MCAO 模型。采用苏木精-伊红染色和膜联蛋白 V/碘化丙啶流式细胞术评价铁蛋白过表达对海马神经元死亡的影响。MWM 试验表明，MCAO 模型降低了大鼠的认知和运动能力，而过表达铁蛋白部分逆转了 MCAO 的作用。此外，MCAO 引起的 tau 过度磷酸化也被铁蛋白所减少。铁蛋白明显恢复了海马神经元的病理性改变、活力受损、凋亡增加和 caspase-9 切割升高。此外，MCAO 模型诱导的活性氧产生和谷胱甘肽消耗也得到了铁蛋白的改善。此外，两个铁死亡的关键调节因子 p53 和 SLC7A11，被证明是由 MCAO 模型上调，而被铁蛋白下调。铁蛋白的减少对于脑缺血诱导的通过 p53 和 SLC7A11 介导的海马神经元铁死亡是必需的。
