2-Iodomelatonin上调NRF2表达对缺血性脑损伤神经保护作用

Up-regulation of NRF2 by 2-Iodomelatonin plays a neuroprotective role in ischemic brain injury

目的探讨褪黑激素受体1(MT1)激动剂2-Iodomelatonin通过上调核因子E2相关因子2(NRF2)对大脑中动脉栓塞小鼠的神经保护作用。方法采用大脑中动脉栓塞(MCAO)法制备小鼠缺血性脑损伤体内模型,给予2-Iodomelatonin及NRF2抑制剂(Nrf2-IN-1)干预。采用三苯基氯化四氮唑(TTC)染色法检测小鼠大脑的梗死体积,Western Blot法检测缺血损伤后大脑皮质半暗带NRF2表达水平,改良神经功能缺损程度评分(mNSS)评估2-Iodomelatonin和Nrf2-IN-1干预对小鼠缺血性脑损伤亚急性期运动功能的影响。结果TTC染色结果显示,2-Iodomelatonin干预可以显著降低缺血性脑损伤小鼠的大脑梗死体积(F=7.79,q=5.06,P<0.05)。Western Blot结果显示,2-Iodomelatonin干预可上调小鼠皮质梗死半暗带NRF2的表达水平(F=10.56,q=3.99,P<0.05)。mNSS评分结果显示,2-Iodomelatonin干预可以显著改善缺血性脑损伤第14天的运动功能损伤(F=6.12,q=4.79,P<0.05),该效应可被Nrf2-IN-1逆转(q=3.60,P<0.05)。结论2-Iodomelatonin干预可以通过上调NRF2降低缺血性脑损伤小鼠的大脑梗死体积并改善14 d时的运动功能损伤。

Objective To study the neuroprotective effect of 2-Iodomelatonin as the agonist of melatonin receptor 1 in mice with middle cerebral artery occlusion by up-regulating nuclear factor erythroid 2-related factor 2(NRF2).Methods The in vivo model of ischemic brain injury in mice was constructed by middle cerebral artery occlusion(MCAO).The interventions consisted of 2-Iodomelatonin and NRF2 inhibitor(Nrf2-IN-1).The infarct volume in mouse brain was determined by triphenyl tetrazolium chloride staining.Western Blot was used to measure the expression levels of NRF2 in the cerebral cortical penumbra after ischemic brain injury.The effects of 2-Iodomelatonin and Nrf2-IN-1 on the motor function of mice in the subacute stage of ischemic brain injury were evaluated by the modified neurological deficit score(mNSS).Results The staining showed that 2-Iodomelatonin could significantly reduce the cerebral infarct volume in mice with ischemic brain injury(F=7.79,q=5.06,P<0.05).Western Blot showed that 2-Iodomelatonin up-regulated the expression level of NRF2 in the cerebral cortical penumbra in mice(F=10.56,q=3.99,P<0.05).The mNSS scores showed that 2-Iodomelatonin could significantly improve the motor functions at 14 d after ischemic brain injury(F=6.12,q=4.79,P<0.05),and this effect could be reversed by Nrf2-IN-1(q=3.60,P<0.05).Conclusion 2-Iodomelatonin can reduce cerebral infarct volume and improve 14-day motor function in mice with ischemic brain injury by up-re-gulating NRF2.