摘要
目的 探究核因子E2相关因子2/血红素加氧酶-1(Nuclear factorNF-E2-related factor 2/heme oxygenase,Nrf2/HO-1)信号通路对帕金森病(Parkinson's disease,PD)模型小鼠行为学障碍的改善作用及其调控机制.方法 制备小鼠 1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-Methyl-4-phenyl-1,2,3,6-tetrahydro pyri-dine,MPTP)模 型,并给予Nrf2抑制剂ML385或铁死亡抑制剂Ferrostatin-1;实验结束后评估各组小鼠行为学表型、多巴胺能神经元损伤程度、氧化应激水平、Nrf2/HO-1信号通路和铁死亡指标表达水平.结果 在MPTP小鼠模型中ML385加剧MPTP组小鼠行为学障碍及酪氨酸轻化酶(Tyrosine hydroxylase,TH)阳性神经元丢失,进一步诱导Fe2+沉积、活性氧(Reactive oxygen species,ROS)合成及丙二醛(Malondialdehyde,MDA)分泌,降低超氧化物歧化酶(Superoxide dismutase,SOD)和谷胱甘肽(Glutathione,GSH)的水平,增加醜基辅酶 A 合成酶长链家族成员 4(Acyl coenzyme a synthetase long chain family member 4,ACSL4)的蛋白表达,并抑制溶质载体家族7成员11(Solute carrier family 7 member 11,SLC7A11)和谷胱甘肽过氧化酶4(Glutathione peroxidase 4,GPX4)的蛋白表达;给予Ferrostatin-1后可取消上述ML385介导的神经损伤作用,同时不影响Nrf2和HO-1的蛋白表达水平.结论 Nrf2/HO-1信号通路能够改善PD模型小鼠行为学障碍,其机制可能与抑制神经元铁死亡有关.
Abstract
Objective The purpose of this study is to investigate the ameliorative effects and the regula-tory mechanisms of Nrf2/HO-1 signal pathway on behavioral dysfunction in mouse model of Parkinson's dis-ease(PD).Methods Made preparation of MPTP mice model.In the MPTP mice model,ML385(Nrf2 inhib-itor)or Ferrostatin-1(ferroptosis inhibitor)was administered.Behavioral analysis,dopaminergic neuronal los-ses,oxidative stress,and the expression of the proteins involved in the Nrf2/HO-1 signaling pathway and fer-roptosis were evaluated after the experimental manipulation in mice.Results ML385 exacerbated behavioral deficits,tyrosine hydroxylase(TH)-positive neuronal losses,also further led to the overloaded iron deposi-tion,ROS accumulation and Malondialdehyde(MDA)excretion.Meanwhile,ML385 decreased the level of SOD and glutathione(GSH),increased the protein expression of ACSL4 and the suppressed the protein ex-pression of SLC7A11 and GPX4 in mouse model of PD.By contrast,administration of Ferrostatin-1 abolished the above M L385-mediated neurological damage effects without affecting the protein expression levels of Nrf2 and HO-1.Conclusion Nrf2/HO-1 signal pathway can improve behavioral impairment in MPTP-induced mice,and perhaps its mechanism is related to inhibiting ferroptosis of dopaminergic neuron.
基金项目
河北省卫健委项目(202105148)
沧州市科技计划项目(21422083136)
邯郸市科学技术研究与发展项目(21422083136)
维普
万方数据