[Research research on the use of melatonin in combination with therapeutic hypothermia for the treatment of neonatal hypoxic-ischemic encephalopathy]

Abstract

Neonatal hypoxic-ischemic encephalopathy (HIE) remains one of the leading causes of death and long-term neurodevelopmental disorders in full-term neonates, and there is currently no curative treatment. Therapeutic hypothermia is now a standard therapy for HIE in the neonatal intensive care unit, but its safety and efficacy in remote areas remains unclear. Melatonin is an indole endocrine hormone mainly produced by the pineal gland and it has the ability to easily penetrate the blood-brain barrier. Through receptor and non-receptor mechanisms, melatonin exerts anti-oxidative and anti-inflammatory effects and participates in the regulation of organelle function and the inhibition of cell death. Melatonin is considered one of the most promising drugs for the treatment of HIE based on its reliable safety profile and clinical/preclinical results. This article reviews the recent research on the use of melatonin in combination with therapeutic hypothermia for the treatment of neonatal HIE.

Keywords: Hypoxic-ischemic encephalopathy; Melatonin; Neonate; Treatment.

图1. MT和TH治疗HIE的机制

红色“T”代表MT参与抑制，红色箭头代表MT参与促进，绿色“T”代表TH参与抑制。［Glu］谷氨酸；［NMDA］N-甲基-D-天冬氨酸；［iNOS］诱导型一氧化氮合酶；［Ca²⁺］钙离子；［ATP］三磷酸腺苷；［NO］一氧化氮；［O^2-］过氧根离子；［ONOO^-］过氧亚硝酸根离子；［OH·］羟基；［CAT］过氧化氢酶；［SOD］超氧化物歧化酶；［MT］褪黑素；［MT1］褪黑素受体1；［AFMK］N1-乙酰-N2-甲酰-5-甲氧基犬尿胺；［AMK］N1-乙酰-5-甲氧基犬尿胺；［ΔΨm］膜电位；［CytC］细胞色素C；［Bax］B淋巴细胞瘤-2相关X蛋白；［mPTP］线粒体通透性转换孔；［caspase］胱天蛋白酶；［ER］内质网；［UPR］未折叠蛋白反应；［PERK］蛋白激酶R样内质网激酶；［IRE1］肌醇需要酶1；［ATF6］活化转录因子6；［CHOP］C/EBP同源蛋白；［NF-κB］核因子-κB；［HIF-1］缺氧诱导因子；［Sirt1］沉默信息调节因子1；［TLR4］Toll样受体4；［TNF-α］肿瘤坏死因子-α；［IL］白细胞介素；［GSDMD］消皮素D；［NLRP3］核苷酸结合寡聚化结构域样受体蛋白3；［LC3-Ⅱ］微管相关蛋白1轻链3-Ⅱ。MT与AFMK、AMK能直接消除自由基，或抑制iNOS和钙内流，或提高SOD和CAT活性而间接消除自由基，保护线粒体结构和功能，改善能量供应。MT抑制UPR并下调CHOP、Bax表达，减少mPTP孔道开放，对抗内质网和线粒体相关的细胞凋亡；MT可通过上调LC3-Ⅱ表达促进自噬；MT通过抑制NLRP3避免caspase-1活化，抑制细胞焦亡和炎症因子释放；MT抑制TLR4/caspase-3通路，改变NF-κB、HIF-1、Sirt1在细胞内的分布，抑制炎症反应。TH减少谷氨酸蓄积，抑制NO产生和离子内流，减少自由基，改善能量供应，抑制细胞凋亡。