三氧化物支持延迟的神经炎症和突触完整性损伤,涉及综合应激反应信号传递
bioRxiv : the preprint server for biology
|January 23, 2026
概括
急性三氧化 (ATO) 暴露会触发综合应激反应 (ISR) 和DNA损伤,导致神经毒性延迟和认知缺陷. ISR 抑制剂显示出缓解这些影响的治疗潜力.
科学领域:
- 神经科学是一个神经科学.
- 毒理学 毒理学 毒理学
- 分子生物学分子生物学
背景情况:
- 三氧化 (ATO) 是一种环境毒素,与急性暴露后延迟的神经毒性有关.
- 在ATO诱导的长期神经退行症背后的分子机制尚未完全理解.
研究的目的:
- 为了研究导致急性三氧化暴露后延迟神经毒性的分子途径.
- 探索综合应激反应 (ISR) 抑制的治疗潜力.
主要方法:
- 使用了人类iPSC衍生的神经元和体内小鼠模型 (C57BL/6J).
- 给予一次高剂量的ATO,并评估神经行为和分子变化.
- 分析了ISR信号传递 (PERK,eIF2α,CHOP,ATF4),转录组特征 (RNAseq),DNA损伤和免疫反应 (STING).
- 在小鼠海马细胞中使用ISRIB测试ISR抑制.
主要成果:
- 在暴露后四周的小鼠中,急性ATO暴露诱导了ISR信号和认知缺陷.
- 在接受ATO治疗的小鼠大脑中观察到ISR活性升高,DNA损伤和受STING介导的免疫失调.
- 通过ISRIB缓解ISR激活和保持突触完整性的ISR抑制.
结论:
- 综合应激反应 (ISR) 激活和DNA损伤诱导的免疫失调是ATO诱导延迟神经毒性的关键驱动因素.
- 三氧化物抑制剂代表了一种有前途的治疗策略,用于减轻与三氧化物相关的神经毒性影响.
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