Artesunate alleviates cerebral ischemia/reperfusion injury by suppressing FUNDC1-mediated excessive mitophagy

IF 3.7 3区 医学 Q2 NEUROSCIENCES
Fei Wang, Wenji Zhou, Liqing Huang, Li Sun, Lujun Deng, Liping Li
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Abstract

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.
青蒿琥酯通过抑制fundc1介导的过度线粒体自噬来减轻脑缺血再灌注损伤。
脑缺血再灌注(I/R)损伤是一种致残性神经系统疾病,发病率高。青蒿琥酯是一种水溶性半琥珀酸衍生物,已成为脑I/R损伤的潜在治疗剂。我们的研究努力评估青蒿琥酯在这种情况下的疗效,同时阐明其作用机制。建立大鼠大脑中动脉闭塞/再灌注(MACO)模型和氧糖剥夺/再灌注(OGD/R)刺激PC12细胞模型。采用透射电镜、线粒体膜电位检测、western blotting和实时定量聚合酶链反应(RT-qPCR)分析线粒体自噬过程。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,青蒿琥酯能抑制细胞凋亡和线粒体过度自噬。机械上,青蒿琥酯通过AMPK (AMP-activated protein kinase)-mTOR (mechanistic target of rapamycin)-TFEB (transcription factor EB)信号通路调节含有1 (FUNDC1)的FUN14结构域介导的线粒体自噬。此外,蒿甲醚减少MCAO大鼠的梗死面积,抑制神经功能障碍,增强记忆表现。总之,我们的数据揭示了一种新的机制,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治疗方法。
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来源期刊
Brain Research Bulletin
Brain Research Bulletin 医学-神经科学
CiteScore
6.90
自引率
2.60%
发文量
253
审稿时长
67 days
期刊介绍: The Brain Research Bulletin (BRB) aims to publish novel work that advances our knowledge of molecular and cellular mechanisms that underlie neural network properties associated with behavior, cognition and other brain functions during neurodevelopment and in the adult. Although clinical research is out of the Journal''s scope, the BRB also aims to publish translation research that provides insight into biological mechanisms and processes associated with neurodegeneration mechanisms, neurological diseases and neuropsychiatric disorders. The Journal is especially interested in research using novel methodologies, such as optogenetics, multielectrode array recordings and life imaging in wild-type and genetically-modified animal models, with the goal to advance our understanding of how neurons, glia and networks function in vivo.
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