缺氧诱导因子信号通路激活与缺血缺氧性脑病的研究进展

Research progress on hypoxia-inducible factor signaling pathway activation and ischemic-hypoxic encephalopathy

缺血缺氧性脑病(HIE)具有高发病率、高病残率、高死亡率等特点,是中枢神经系统最为常见的一类疾病,具体是指由急性脑缺氧造成的脑损伤和由此引发的一系列神经症状的一种临床综合征,患者通常出现癫痫、脑瘫、行为障碍等神经系统后遗症。缺氧诱导因子(HIF)是内源性氧感应系统的组成部分,属于异二聚体转录因子,由O2敏感的α亚基和组成型表达的β亚基组成,通过调节血管生成、红细胞生成和代谢中缺氧转录过程,参与检测和适应细胞缺氧状态。基于HIF信号通路的激活,许多研究都集中在选择性小分子药物的开发,以期治疗HIE。本文就HIF及其相关信号通路激活在HIE中的具体机制作一系统综述,并对可能的相关新型小分子抑制剂及中药化合物在HIE中的潜在治疗应用进行介绍,为治疗HIE提供新思路。

Hypoxic ischemic encephalopathy(HIE)has the characteristics of high incidence,high morbidity and high mortality,and is the most common type of disease of the central nervous system,specifically referring to a clinical syndrome of brain damage caused by acute cerebral hypoxia and a series of neurological symptoms caused by it.Patients usually have neurological sequelae such as epilepsy,cerebral palsy,and behavioral disorders.Hypoxia inducible factor(HIF)is a component of the endogenous oxygen sensing system belonging to heterodimeric transcription factors,which are composed of O2-sensitiveαsubunits and constitutively expressedβsubunits,and participate in the detection and adaptation of cellular oxygen stress responses by regulating angiogenesis,erythropoiesis,and hypoxic transcription processes in metabolism.Based on the activation of the HIF signaling pathway,many studies have focused on the development of selective small molecule drugs to treat HIE.This review summarizes the molecular basis of HIF and the specific mechanism of HIF-related signaling pathway activation in HIE,and introduces the potential therapeutic applications of related novel small molecule inhibitors and Chinese herbs compounds in HIE,so as to provide new ideas for the treatment of HIE.