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<p>Neurodegenerative diseases represent significant global health challenges, with rising incidence rates. A substantial body of evidence indicates that excitotoxicity may be a critical target in the context of these diseases. However, effective pharmacological interventions aimed at mitigating excitotoxicity remain elusive. This study aimed to elucidate the neuroprotective effects and mechanisms of the mitochondrion-targeted NOX inhibitor, mito-apocynin, in the context of kainic acid (KA)-induced excitotoxicity. Our findings demonstrate that KA disrupts mitochondrial morphology, leading to impaired energy metabolism and mitochondrial dysfunction. Western blotting experiments revealed that KA compromises mitochondrial quality control. Additionally, Nissl staining and CCK8 assays indicated that mito-apocynin (administered at 75&#xa0;μg/kg <i>in vivo</i> and 1&#xa0;μM <i>in vitro</i>) significantly reduced neuronal death resulting from KA-induced excitotoxic damage in both <i>in vivo</i> and <i>in vitro</i> models. Furthermore, mito-apocynin improved neurobehavioral deficits induced by KA and mitigated mitochondrial dysfunction observed <i>in vitro</i>. Notably, mito-apocynin significantly reversed the KA-induced increase in NOX4 levels within the striatal mitochondria, reduced the ratio of phosphorylated DRP1 (Ser616) to total DRP1, and enhanced the expression of PGC-1α, PINK1, and Parkin proteins throughout the total striatum. In summary, mito-apocynin alleviates oxidative stress, preserves normal mitochondrial function and energy metabolism, and promotes mitochondrial quality control by modulating NOX expression in mitochondria, thereby reducing KA-induced excitotoxic damage.</p>

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Mito-Apocynin Protects Against Kainic Acid-Induced Excitotoxicity by Ameliorating Mitochondrial Impairment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月17日

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  • Miaomiao Lin,
  • Huanchen Wu,
  • Xiaorui Wan,
  • Na Liu,
  • Yiyue Jiang,
  • Yichao Sheng,
  • Jing Wang,
  • Haidong Xu,
  • Jie Xue,
  • Zhenghong Qin,
  • Yan Wang

摘要

Neurodegenerative diseases represent significant global health challenges, with rising incidence rates. A substantial body of evidence indicates that excitotoxicity may be a critical target in the context of these diseases. However, effective pharmacological interventions aimed at mitigating excitotoxicity remain elusive. This study aimed to elucidate the neuroprotective effects and mechanisms of the mitochondrion-targeted NOX inhibitor, mito-apocynin, in the context of kainic acid (KA)-induced excitotoxicity. Our findings demonstrate that KA disrupts mitochondrial morphology, leading to impaired energy metabolism and mitochondrial dysfunction. Western blotting experiments revealed that KA compromises mitochondrial quality control. Additionally, Nissl staining and CCK8 assays indicated that mito-apocynin (administered at 75 μg/kg in vivo and 1 μM in vitro) significantly reduced neuronal death resulting from KA-induced excitotoxic damage in both in vivo and in vitro models. Furthermore, mito-apocynin improved neurobehavioral deficits induced by KA and mitigated mitochondrial dysfunction observed in vitro. Notably, mito-apocynin significantly reversed the KA-induced increase in NOX4 levels within the striatal mitochondria, reduced the ratio of phosphorylated DRP1 (Ser616) to total DRP1, and enhanced the expression of PGC-1α, PINK1, and Parkin proteins throughout the total striatum. In summary, mito-apocynin alleviates oxidative stress, preserves normal mitochondrial function and energy metabolism, and promotes mitochondrial quality control by modulating NOX expression in mitochondria, thereby reducing KA-induced excitotoxic damage.