DL ‐3‐n‐Butylphthalide Protects Mitochondria Against Ischemia/Hypoxia Damage via Suppressing GCN5L1 ‐Mediated Drp1 Acetylation in Neurons and Mouse Brains

作者：Haitao Zhang, Ning Zhang, Xiaotong Yang, Jiejie Zhang, Xiaoli Ge, Lei Wang, Shan Wang, Ya Wen · 发表于：CNS Neuroscience & Therapeutics · 年份：2025 · DOI：10.1002/cns.70682 · 被引用次数：3 · 研究领域：Neurological Disease Mechanisms and Treatments、Cerebrovascular and Carotid Artery Diseases、Traditional Chinese Medicine Analysis

BACKGROUND: Mitochondrial dysfunction is an initial event of the cascade reactions triggered by ischemic stroke, contributing to the pathogenesis of ischemic brain injury. DL-3-n-butylphthalide (NBP), a compound originally isolated from the seeds of Apium graveolens Linn, exerts neuroprotective effects by improving mitochondrial function in ischemic brain tissues; however, the exact molecular mechanisms underlying its action remain poorly understood. METHODS: The OGD-exposed neuronal cells and dMCAO mice were used to investigate the effects of ischemia/hypoxia on mitochondrial function and the protective action of NBP on mitochondrial damage. Co-immunoprecipitation and immunofluorescence staining were performed to identify the interaction between Drp1 and GCN5L1. Western blotting, immunofluorescence and immunohistochemical staining were conducted to detect the expression of GCN5L1, Drp1, ERK1/2, Bax, Bcl2, and caspase-3. The mitochondrial function was analyzed by measuring mitochondrial ROS, ATP production, mitochondrial membrane potential (MMP) and mPTP opening. RESULTS: We observed that mitochondrial dysfunction occurs in OGD-treated neuronal cells and brain tissues of dMCAO mice, as evidenced by the alteration in the mPTP, MMP, ATP content, and ROS levels, which are accompanied by a significant increase in mitochondrial fission and neuronal apoptosis, as shown by TUNEL staining and the changes in Bcl-2, Bax and caspase-3 expression. Importantly, NBP intervention significan...