Wang Fei, Zhou Wenji, Huang Liqing, Sun Li, Deng Lujun, Li Liping
Department of Acupuncture and Rehabilitation, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China.
Department of Acupuncture and Rehabilitation, Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University, Hangzhou, China.
Brain Res Bull. 2025 Aug;228:111407. doi: 10.1016/j.brainresbull.2025.111407. Epub 2025 May 30.
Cerebral ischemia-reperfusion (I/R) injury represents a debilitating neurological disorder with significant morbidity. Artesunate, a water-soluble hemisuccinate derivative, has emerged as a potential therapeutic agent for cerebral I/R injury. Our investigation endeavors to assess the efficacy of artesunate in this context while elucidating its mechanisms of action. We established the middle cerebral artery occlusion/refusion (MACO) rat model and oxygen-glucose deprivation/reperfusion (OGD/R)-stimulated PC12 cells model. Mitophagy was analyzed by transmission electron microscope, mitochondrial membrane potential detection, western blotting, and real-time quantitative polymerase chain reaction (RT-qPCR). The underlying mechanism was investigated by cell viability, flow cytometry, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. The results suggested that artesunate inhibited apoptosis and excessive mitophagy. Mechanically, artesunate regulated FUN14 domain containing 1 (FUNDC1)-mediated mitophagy via the AMPK (AMP-activated protein kinase)-mTOR (mechanistic target of rapamycin)-TFEB (transcription factor EB) signaling pathway. Additionally, artemether reduced the infarct size in MCAO rats, inhibited neurological dysfunction, and enhanced memory performance. In summary, our data revealed a novel mechanism whereby artesunate suppresses apoptosis by inhibiting excessive mitophagy. These findings offered a new promising therapy for cerebral I/R injury.
脑缺血再灌注（I/R）损伤是一种致残性神经系统疾病，发病率很高。青蒿琥酯是一种水溶性半琥珀酸衍生物，已成为治疗脑I/R损伤的潜在药物。我们的研究旨在评估青蒿琥酯在此背景下的疗效，并阐明其作用机制。我们建立了大脑中动脉闭塞/再灌注（MACO）大鼠模型和氧糖剥夺/再灌注（OGD/R）刺激的PC12细胞模型。通过透射电子显微镜、线粒体膜电位检测、蛋白质印迹法和实时定量聚合酶链反应（RT-qPCR）分析线粒体自噬。通过细胞活力、流式细胞术和末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）染色研究其潜在机制。结果表明，青蒿琥酯抑制细胞凋亡和过度的线粒体自噬。机制上，青蒿琥酯通过AMPK（AMP激活的蛋白激酶）-mTOR（雷帕霉素作用靶点）-TFEB（转录因子EB）信号通路调节含FUN14结构域蛋白1（FUNDC1）介导的线粒体自噬。此外，蒿甲醚减小了MCAO大鼠的梗死面积，抑制了神经功能障碍，并增强了记忆能力。总之，我们的数据揭示了一种新机制，即青蒿琥酯通过抑制过度的线粒体自噬来抑制细胞凋亡。这些发现为脑I/R损伤提供了一种新的有前景的治疗方法。
