4⁃辛基衣康酸通过Keap1/Nrf2/GPX4通路减少癫痫大鼠海马神经元铁死亡  

4⁃octyl itaconate reduces ferroprosis of hippocampal neurons in chronic epileptic rats via Keap1/Nrf2/GPX4 pathway

作　　者：章朝 王梓 宁瑞 吴淑华[2] 胡忠波[1] 郭翀 郭科[1] 李建民[1] ZHANG Zhao;WANG Zi;NING Rui;WU Shuhua;HU Zhongbo;GUO Chong;GUO Ke;LI Jianmin(Department of Neurosurgery,Binzhou 256600;Department of Pathology,Affiliated Hospital of Binzhou Medical University,Binzhou 256603,China)

机构地区：[1]滨州医学院附属医院神经外科,滨州256603 [2]滨州医学院附属医院病理科,滨州256603

出　　处：《神经解剖学杂志》2023年第4期443-451,共9页Chinese Journal of Neuroanatomy

基　　金：山东省医药卫生科技发展计划(2017WS553)。

摘　　要：目的:探讨4⁃辛基衣康酸(4⁃OI)对癫痫大鼠海马神经元铁死亡的影响。方法:雄性SD大鼠45只,随机分为生理盐水组、戊四氮组(PTZ)和4⁃辛基衣康酸和戊四氮联合治疗组(4⁃OI+PTZ)。观察记录各组大鼠癫痫发作程度行为学及脑电图变化,应用尼氏染色观察海马区神经元变化,膜片钳技术评估海马CA1区的神经元兴奋性,试剂盒测定海马区铁离子、谷胱甘肽(GSH)和丙二醛(MDA)水平,采用免疫组化与Western Blot检测各组大鼠海马区神经元核因子红细胞2相关因子2(Nrf2)、Klech样ECH关联蛋白1(Keap1)、谷胱甘肽过氧化物酶4(GPX4)、前列腺素内过氧化物合成酶2(PTGS2)的表达情况。结果:与生理盐水组比较,PTZ组癫痫样发作明显,神经元尼氏体的含量显著减少,神经元的兴奋性显著增加,海马区铁离子、MDA、PTGS2与Keap1的表达明显升高,GSH、Nrf2、GPX4的表达明显下降(P<0.05);与癫痫组相比,4⁃OI处理组癫痫发作等级降低,神经元尼氏体的含量显著增加,神经元的兴奋性显著下降,海马区铁离子、MDA、PTGS2与Keap1的表达明显下降,GSH、Nrf2与GPX4的表达明显升高(P<0.05)。结论:4⁃OI可以通过抑制癫痫模型大鼠海马组织中Keap1的活性,进而上调Nrf2和GPX4表达,抑制神经元铁死亡并缓解癫痫发作。Objective:To investigate the effect of 4⁃octyl itaconate(4⁃OI)on ferroptosis of hippocampal neurons in chronic epileptic rats.Methods:Forty⁃five male SD rats were randomly divided into control group,4⁃octyl itaconate(4⁃OI)+PTZ group and pentylenetetrazol(PTZ)group.The changes of behavior and electroencephalogram(EEG)changes of epileptic seizure severity were observed and recorded in each group of rats.Nissl staining was performed to observe the neurons in the hippocampus,Patch clamp was used to evaluate the excitability of neurons in CA1 area,The kit was used to determine the levels of Fe2+,glutathione(GSH),and malondialdehyde(MDA)in the hippocampus.Immunohistochemistry and Western Blot were performed to detect the expression of kelch kelch⁃like ECH associated pro⁃tein 1(Keap1),nuclear factor erythroid 2⁃related factor 2(Nrf2),glutathione peroxidase 4(GPX4)and prostaglandin endoperoxide synthase 2(PTGS2)in hippocampal region of rats in each group.Results:Compared with control group,It’s more obvious of epileptic seizure for rats in PTZ group,the Nissl body decreased significantly,the excitability of neurons increased significantly,the expressions of Fe2+,MDA,PTGS2,and Keap1 increased significantly,the expres⁃sions of GSH,Nrf2 and GPX4 decreased significantly(P<0.05).However,when rats were injected with 4⁃OI com⁃pared with the epilepsy group,the seizure intensity decreased,and the Nissl body increased significantly,the excitabili⁃ty of neurons decreased significantly,the expression of Fe2+,MDA,PTGS2 and Keap1 in hippocampus decreased sig⁃nificantly,the expression of GSH,Nrf2 and GPX4 increased significantly(P<0.05).Conclusion:4⁃OI can inhibit the activity of Keap1 in the hippocampus of epilepsy model rats,thereby up⁃regulating the expression of Nrf2 and GPX4,reducing neuronal ferroptosis and relieving seizures.

关 键 词：癫痫 戊四氮 Keap1/Nrf2/Gpx4通路 铁死亡 4⁃辛基衣康酸 大鼠 

分 类 号：R742.1[医药卫生—神经病学与精神病学] R-332[医药卫生—临床医学]