Bai Hui, Du Shan, Qiu Di, Li Siyao, Gao Ruifeng, Zhang Zhiheng
College of Veterinary Medicine, Inner Mongolia Agricultural University, Hohhot, China.
College of Veterinary Medicine, Northeast Agricultural University, Harbin, China.
Mol Neurobiol. 2025 May 23. doi: 10.1007/s12035-025-05042-w.
Increasing evidence reveals that multiple or prolonged exposure to ketamine causes hippocampal damage and cognitive dysfunction. However, the critical mechanisms underlying ketamine-induced neurotoxicity in the developing brain remain elusive. The present study was designed to investigate the role of GPX4 in ketamine-induced pyroptosis and cognitive dysfunction in the developing rat hippocampus. To achieve this goal, we conducted Western blotting, ELISA tests, histopathological analysis, Morris water maze tests, cell viability assays, and biochemical analyses on PC12 cells, HAPI cells, and 7-day-old rats. Additionally, N-acetylcysteine (NAC) and RSL3 were administered prior to continuous ketamine exposure. Our findings indicate that GPX4 inhibition by RSL3 enhances lipid peroxidation and mitochondrial damage, activates NLRP3/caspase-1 axis-dependent pyroptosis, and exacerbates hippocampal damage and cognitive dysfunction following ketamine exposure, while NAC effectively mitigates the effects of RSL3. Collectively, our in vivo and in vitro results support the notion that GPX4 may serve as a negative regulator of pyroptosis in ketamine-induced hippocampal damage and cognitive dysfunction. Our study proposes a novel strategy for treating ketamine-induced neurotoxicity through upregulating GPX4 expression.
越来越多的证据表明，多次或长期接触氯胺酮会导致海马体损伤和认知功能障碍。然而，发育中的大脑中氯胺酮诱导神经毒性的关键机制仍不清楚。本研究旨在探讨谷胱甘肽过氧化物酶4（GPX4）在氯胺酮诱导的发育中大鼠海马体焦亡和认知功能障碍中的作用。为实现这一目标，我们对PC12细胞、HAPI细胞和7日龄大鼠进行了蛋白质免疫印迹法、酶联免疫吸附测定、组织病理学分析、莫里斯水迷宫试验、细胞活力测定和生化分析。此外，在连续氯胺酮暴露之前给予N-乙酰半胱氨酸（NAC）和RSL3。我们的研究结果表明，RSL3抑制GPX4会增强脂质过氧化和线粒体损伤，激活NLRP3/半胱天冬酶-1轴依赖性焦亡，并加剧氯胺酮暴露后的海马体损伤和认知功能障碍，而NAC可有效减轻RSL3的作用。总的来说，我们的体内和体外研究结果支持这样一种观点，即GPX4可能是氯胺酮诱导的海马体损伤和认知功能障碍中焦亡的负调节因子。我们的研究提出了一种通过上调GPX4表达来治疗氯胺酮诱导的神经毒性的新策略。
