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首页> 外文期刊>Experimental Neurology >Simvastatin preconditioning confers neuroprotection against hypoxia-ischemia induced brain damage in neonatal rats via autophagy and silent information regulator 1 (SIRT1) activation
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Simvastatin preconditioning confers neuroprotection against hypoxia-ischemia induced brain damage in neonatal rats via autophagy and silent information regulator 1 (SIRT1) activation

机译：Simvastatin预处理通过自噬和静音信息调节器1（SIRT1）激活来赋予NeuroProtoction对缺氧缺血诱导的新生大鼠脑损伤

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摘要

Previous studies have shown that simvastatin (Sim) has neuroprotective effects in a neonatal model of hypoxia-ischemia (HI)-induced brain injury when administered before but not after HI, pointing to the preconditioning (PC)-like effects of the statin. The present study aimed to gain more insight into the PC-like effect of Sim by studying the role of autophagy and its modulation by mTOR and SIRT1 in neuroprotection. Sim potentiated the autophagy response induced by neonatal HI, as shown by the increased expression of both microtubule-associated protein 1 light chain 3 (LC3) and beclin 1, increased monodansylcadaverine (MDC) labeling, and reduced expression of p62. The autophagy inhibitor 3-methyladenine (3MA) completely blocked the neuroprotective effect of Sim. Two hours after HI, there was a reduction in the activity of mTORC1 and a concomitant increase in that of mTORC2. Sim preconditioning further decreased the activity of mTORC1, but did not affect that of mTORC2. However, 24 h after injury, mTORC2 activity was significantly preserved in Sim-treated rats. Sim preconditioning also prevented the depletion of SIRT1 induced by HI, an effect that was completely blocked by 3MA. These data show that Sim preconditioning may modulate autophagy and survival pathways by affecting mTORC1, mTORC2, and SIRT1 activities. This study provides further preclinical evidence of the PC-like effect of statins in brain tissue, supporting their beneficial effects in improving stroke outcome after prophylactic treatments.
机译：以前的研究表明，辛伐他汀（SIM）在缺氧缺血（HI）诱导的脑损伤的新生儿模型中具有神经保护作用，但在HI之后施用时，指向他汀类药物的预处理（PC）效应。本研究旨在通过研究自噬和SIRT1在神经保护中的MTOR和SIRT1的作用，获得更多地洞察SIM的PC样效果。 SIM激增了新生儿HI诱导的自噬反应，如微管相关蛋白1轻链3（LC3）和BECLIN1的增加表达，增加了单倍二酰甲酰胺（MDC）标记，并降低了P62的表达。自噬抑制剂3-甲基腺嘌呤（3mA）完全阻断了SIM的神经保护作用。 HI后两小时，MTORC1的活性降低了MTORC2的伴随增加。 SIM预处理进一步降低了MTORC1的活性，但不影响MTORC2的活动。然而，24小时损伤后，MTORC2活性在SIM处理的大鼠中得到了显着保存。 Sim预处理还防止了HI诱导的SIRT1的耗竭，其效果完全被3mA封闭。这些数据显示SIM预处理可以通过影响MTORC1，MTORC2和SIRT1活动来调制自噬和生存途径。本研究提供了脑组织中毒素的PC样效果的进一步临床前验证，支持其在预防治疗后改善中风结果方面的有益作用。

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