内源性硫化氢对高热惊厥脑损伤大鼠内质网应激GRP78-eIF2α-PERK-CHOP通路的作用

Febrile seizure (FS) is one of the most common seizure disorders in children. The molecular mechanisms underlying recurrent FS and the pathogenesis of the brain damage induced by recurrent FS remain obscure. Endoplasmic reticulum stress is demonstrated to play important roles in the development of recurrent FS and related brain damage. Recent studies suggested that H2S modulates endoplasmic reticulum stress in cardiovascular disease and diabetes. Whether H2S modulates endoplasmic reticulum stress in the pathogenesis of recurrent FS is not clear. On a rat model of recurrent FS, the present study aims to explore the effect of H2S on GRP78(glucose regulated protein 78)-eIF2α(pancreatic eukaryotic translation initiation factor 2 subunit α)-PERK (RNA-dependent protein kinase-like ER protein kinase)-CHOP(C/EBP homologous protein) pathway, and further evaluate the alteration of the seizure latency, the seizure duration，the seizure intensity, the ultrastructural changes of the neurons in the cerebral cortex and hippocampus,the development of mossy ?ber sprouting in hippocampus, the ability of learning and memory of the rats after the modulation of GRP78-eIF2α-PERK-CHOP by H2S. The changes in neuronal excitability, neuronal activity, neuronal apoptosis and mitochondrial activity of the neurons in the cerebral cortex and hippocampus of the rats are also examined. On the basis of previous studies, the present study attempts to deepen the understanding of the pathogenesis of recurrent FS and related brain damage in view of gaseous signal molecule H2S and endoplasmic reticulum stress, and strive to explore a new breakthough in management of brain damage induced by recurrent FS.

高热惊厥脑损伤是小儿脑损伤的常见原因，其发病机制需深入研究。研究提示，在高热惊厥脑损伤发病中，硫化氢（H2S）和内质网应激起到重要作用，但机制不明。H2S在心血管病和糖尿病中对内质网应激有调控作用。H2S是否在高热惊厥脑损伤中对内质网应激发挥调控作用不清楚。本研究利用高热惊厥动物模型, 研究H2S对内质网应激通路内质网分子伴侣糖调节蛋白78（GRP78）-真核细胞翻译起始复合体eIF2α-PEK样内质网激酶(PERK)-生长控制损伤基因CHOP的作用；研究在H2S对GRP78-eIF2α-PERK-CHOP通路调控后，高热惊厥大鼠的惊厥潜伏期、惊厥持续时间、惊厥程度、皮层和海马超微结构、海马苔藓纤维发芽情况、学习记忆能力，以及大鼠大脑皮层和海马的神经元兴奋性、神经元活力、神经元凋亡和线粒体活性的变化。在既往研究基础上，从气体信号分子H2S和内质网应激角度深化对高热惊厥脑损伤分子机制的认识。

高热惊厥脑损伤是儿童时期脑损伤的常见原因之一，其发病机制需要深入研究。既往的研究提示，在高热惊厥脑损伤发病中，硫化氢（H2S）和内质网应激起到重要作用，但机制不明。H2S在心血管病和糖尿病中对内质网应激有调控作用。H2S是否在高热惊厥脑损伤中对内质网应激发挥调控作用目前尚不清楚。本研究成功建立了高热惊厥动物模型，利用此模型研究反复高热惊厥脑损伤发病机制中内源性H2S/CBS体系对内质网应激通路GRP78-eIF2α-PERK-CHOP的调控作用。结果发现，内源性H2S/CBS体系和内质网应激通路GRP78-eIF2α-PERK-CHOP均在高热惊厥脑损伤的发病机制中发挥了重要作用。进一步的研究发现，内源性H2S是通过抑制GRP78-eIF2α-PERK-CHOP信号通路在高热惊厥脑损伤的发病机制中发挥作用。完成上述研究后，结合我们既往的研究结果和查阅文献，发现气体信号分子一氧化碳和二氧化硫可能参与了反复高热惊厥脑损伤的发病过程，从而增加了这部分研究。结果发现，内源性一氧化碳通过调控内质网应激GRP78-eIF2α-PERK-CHOP信号通路在高热惊厥脑损伤的发病机制中发挥作用；内源性二氧化硫在高热惊厥脑损伤发病机制中的作用存在浓度依赖性。本项目研究结果从气体信号分子和内质网应激角度深化对高热惊厥脑损伤分子机制的认识，为高热惊厥脑损伤机制的研究揭开一新的篇章。