SIRT1/NF-kB信号调控在褪黑素对SAH线粒体氧化应激和早期脑损伤中作用研究

Cerebral subarachnoid hemorrhage (SAH) has a very high incidence of death and disability, and its pathological mechanism is complex. The early brain injury in three days is very critical to prognosis. Mitochondrial oxidative stress plays a key progress. SIRT1, which has the activity of deacetylase, is a multifunctional transcription factor. Activation of SIRT1 inhibits oxidative stress injuries mediated by NF-κB and others. The neuroprotective effect SIRT1 is causing a widespread concern. Melatonin is the most potent and endogenous free radical scavenger. We recently found that melatonin could reduce cerebral ischemia by increasing SIRT1 expression, and it could reduce SAH early brain injury by regulating NF-κB and other anti-inflammatory molecules. These results suggested that SIRT1/NF-κB pathway plays a important role in mitochondrial oxidative stress in melatonin reducing SAH early brain injury. But the specific mechanisms are unclear. So from the molecular, cellular and body level, the study will use SIRT1 knockout, transgenic mice and cell models to research the SIRT1 role in SAH early brain injury; and NF-κB / SIRT1 regulation mechanisms participated in SAH early brain injury; and whether melatonin will reduce cerebral oxidative stress of SAH by regulation SIRT1 / NF-κB signal pathway. The project hopes to find a new molecular target to reduce early brain injury of SAH, and provide a theoretical basis for developing those melatonin-based neuroprotective drugs.

脑蛛网膜下腔出血（SAH）死亡率致残率高，病理机制复杂，3天内早期脑损伤对预后关键，且线粒体氧化应激扮演关键角色。SIRT1是有蛋白去乙酰化酶活性的多功能转录调节因子，活化后抑制NF-κB等介导的氧化应激损伤，其神经保护作用广受关注，褪黑素是最强效内源性自由基清除剂。我们近期发现褪黑素上调SIRT1抗脑缺血，并调控NF-κB等炎症分子抗SAH早期脑损伤，提示SIRT1/NF-κB线粒体氧化应激通路在褪黑素抗SAH早期脑损伤中发挥重要作用，但具体机制不清，本研究将采用SIRT1基因敲除、转基因小鼠和细胞模型，从分子、细胞与在体水平研究SIRT1在SAH早期脑损伤中作用； NF-κB/SIRT1调控参与SAH早期脑损伤机制；褪黑素是否通过调控SIRT1/NF-κB信号途径以抗SAH早期脑氧化应激损伤。本项目希望得出新的抗SAH早期脑损伤分子靶点，并为开发以褪黑素为基础的临床脑保护药物提供理论依据。

脑蛛网膜下腔出血（SAH）死亡率致残率高，病理机制复杂，除了脑血管痉挛，近年来研究发现3天内早期脑损伤（EBI）对预后关键，且线粒体氧化应激在其中扮演关键角色。SIRT1是有蛋白去乙酰化酶活性的多功能转录调节因子，活化后抑制相关炎性分子介导的氧化应激损伤，其神经保护作用广受关注，褪黑素是最强效内源性自由基清除剂。我们近期发现褪黑素上调SIRT1抗脑缺血，并调控相关炎症分子抗SAH早期脑损伤，提示SIRT1/炎性分子线粒体氧化应激通路在褪黑素抗SAH早期脑损伤中发挥重要作用，但具体机制不清，本研究通过实验动物学、分子生物学，细胞生物学，神经形态学等实验方法，在动物和细胞水平研究证实了SIRT1在SAH早期脑损伤中起脑保护作用；SIRT1/炎性分子调控参与SAH早期脑损伤过程；褪黑素通过调控SIRT1/炎性分子信号途径，拮抗SAH早期氧化应激损伤起到脑保护作用，褪黑素也可以通过调节AMPK磷酸化缓解氧糖剥夺诱导的HT22细胞凋亡，起到神经保护的作用。本项目结果希望通过研究得出的新抗SAH早期脑损伤分子靶点，为开发以褪黑素为基础的临床脑保护药物提供理论依据。