基于Nrf2/Gpx4通路研究右美托咪定对缺血缺氧性脑损伤新生大鼠铁死亡及神经功能的影响  

Effects of dexmedetomidine on ferroptosis and neurological function of neonatal rats with hypoxic-ischemic brain damage through the Nrf2/Gpx4 signaling pathway

作　　者：丁宁静 李志平 王海霞 DING Ningjing;LI Zhiping;WANG Haixia(Department of Anesthesiology,Huashan Hospital,Fudan University,Shanghai 200040,China;不详)

机构地区：[1]复旦大学附属华山医院麻醉科,上海市200040 [2]杭州医学院基础医学与法医学院

出　　处：《河北医药》2024年第17期2586-2590,共5页Hebei Medical Journal

基　　金：浙江省卫生健康科技计划青年创新人才项目(编号:2022RC129)。

摘　　要：目的基于核因子E2相关因子2(Nrf2)/谷胱甘肽过氧化物酶4(Gpx4)信号通路,研究右美托咪定(DEX)对缺血缺氧性脑损伤(HIBD)新生大鼠铁死亡及神经功能的影响。方法构建HIBD新生大鼠模型,随机分为模型组、DEX(100μg/kg)组、DEX(100μg/kg)+抑制剂(Nrf2抑制剂鸦胆子苦醇2 mg/kg)组,每组12只,另取12只新生大鼠作为对照组。对照组和模型组腹腔注射相同体积的0.9%氯化钠溶液。大鼠神经功能缺损程度评分(NDS)评价大鼠神经功能;氨基酸自动分析仪检测海马组织中谷氨酸(Glu)和γ-氨基丁酸(GABA)水平;尼氏(Nissl)染色检测海马区神经元形态;酶联免疫吸附试验(ELISA)检测海马组织中白细胞介素-6(IL-6)、肿瘤坏死因子-α(TNF-α)、神经元特异性烯醇化酶(NSE)含量;试剂盒检测海马组织丙二醛(MDA)、谷胱甘肽(GSH)、铁含量;蛋白免疫印迹检测海马组织中Nrf2、HO-1、Gpx4、胱氨酸/谷氨酸逆向转运蛋白(xCT)表达情况。结果与对照组比较,模型组海马区神经元形态异常,腹侧神经元轴突长短不一且排布不整齐,部分神经元呈背侧脱离趋势,NDS评分、海马组织中Glu、IL-6、TNF-α、NSE、MDA、铁含量升高(P<0.05),GABA、GSH含量及Nrf2、HO-1、Gpx4、xCT蛋白水平降低(P<0.05);与模型组比较,DEX组海马区神经元形态相对饱满,腹侧神经元轴突较整齐,NDS评分、海马组织中Glu、IL-6、TNF-α、NSE、MDA、铁含量降低(P<0.05),GABA、GSH含量及Nrf2、HO-1、Gpx4、xCT蛋白水平升高(P<0.05);Nrf2抑制剂可减轻DEX对HIBD新生大鼠神经损伤的改善作用(P<0.05)。结论DEX能够激活Nrf2/Gpx4通路,抑制铁死亡,改善HIBD新生大鼠神经损伤。Objective To study the effects of dexmedetomidine(DEX)on ferroptosis and neurological function of neonatal rats with hypoxic-ischemic brain damage(HIBD)through the nuclear factor E2-related factor 2(Nrf2)/glutathione peroxidase 4(Gpx4)signaling pathway.Methods A HIBD model was created in neonatal rats.They were randomly assigned into model group,DEX group(100μg/kg DEX)and DEX+Nrf2 inhibitor group(100μg/kg DEX+Nrf2 inhibitor brucebitol 2mg/kg),with 12 rats in each group.Another 12 neonatal rats were selected as control group.Rats in the control group and model group were intraperitoneally injected with the same volume of normal saline.Neurological deficit score(NDS)was graded to evaluate rat neurological function.An amino acid automatic analyzer was used to measure the levels of glutamate(Glu)andγ-aminobutyric acid(GABA)in the hippocampus.Nissl staining was performed to measure the morphology of neurons in the hippocampus.Enzyme-linked immunosorbent assay(ELISA)was performed to measure the levels of interleukin-6(IL-6),tumor necrosis factor-α(TNF-α)and neuron-specific enolase(NSE)in the hippocampus.Commercial kits were used to measure the contents of malondialdehyde(MDA),glutathione(GSH)and iron in the hippocampus.Western blotting was performed to measure the protein expressions of Nrf2,heme-oxygenase(HO)-1,Gpx4,and cystine/glutamate antiporter(xCT)in the hippocampus.Results Compared with those of the control group,rats in the model group presented an abnormal morphology of hippocampal neurons,varying length of disorderly arranged ventral neurons with dorsal detachment in some neurons,significantly higher NDS score and the contents of Glu,IL-6,TNF-α,NSE,MDA and iron in the hippocampus(P<0.05),but significantly lower contents of GABA and GSH,and protein levels of Nrf2,HO-1,Gpx4,and xCT(P<0.05).Compared with those of the model group,rats in the DEX group had relatively intact neurons in the hippocampus,well arranged axons in the ventral neurons,significantly lower NDS score and the contents of Glu,IL-6,TNF-α,

关 键 词：核因子E2相关因子2 谷胱甘肽过氧化物酶4 铁死亡 右美托咪定 缺血缺氧性脑损伤 新生大鼠 神经功能 

分 类 号：R329.485.2[医药卫生—人体解剖和组织胚胎学]