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目的:探讨高赖氨酸饮食的戊二酰辅酶A脱氢酶(GCDH)基因缺陷(GCDHn -/-)大鼠氧化应激损伤机制及可能通路。n 方法:4周龄雄性SD大鼠按照随机数字表法分为6组：野生型标准饮食(WT)组(n n=6)、纯合子标准饮食(GCDHn -/-)组(n n=11)、野生型高赖氨酸(WT+Lys)组(n n=8)、纯合子高赖氨酸(GCDHn -/-+Lys)组(n n=13)、野生型高赖氨酸加维生素E(WT+Lys+VE)组(n n=7)、纯合子高赖氨酸加维生素E(GCDHn -/-+Lys+VE)组(n n=12)。WT组和GCDHn -/-组给予标准饮食(常规大鼠饲料)，余4组给予4.7%高赖氨酸加强饲料，自由进食水。WT+Lys+VE和GCDHn -/-+Lys+VE组于每天上午10点维生素E[100 mg/(kg·d)]灌胃1次，其余各组等量生理盐水灌胃。观察各组大鼠体质量及存活情况。干预28 d后腹腔注射100 g/L水合氯醛麻醉后断头取脑获取海马组织，通过HE染色观察大鼠海马病理形态学改变；ELISA法检测海马氧化应激指标谷胱甘肽过氧化物酶(GPx)、丙二醛(MDA)、超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、还原型谷胱甘肽(GSH)含量/活性；Western blotting实验检测海马P38、c-Jun N-氨基端激酶(JNK)、细胞外调节蛋白激酶(ERK)蛋白表达情况。n 结果:(1)一般情况：GCDHn -/-+Lys组大鼠存活比例为9/13，GCDHn -/-+Lys+VE组大鼠为11/12。干预第7天开始，GCDHn -/-+Lys组、GCDHn -/-+Lys+VE组大鼠体质量均显著低于WT组，差异有统计学意义(n P<0.05)。(2)应激指标检测结果：与WT组相比，GCDHn -/-+Lys组和GCDHn -/-+Lys+VE组大鼠海马组织MDA含量显著增加，差异有统计学意义(n P<0.05)。与WT组比较，GCDHn -/-+Lys组大鼠GPx活性、CAT活性、SOD活性显著减弱，GSH含量显著减少，差异有统计学意义(n P<0.05)；与GCDHn -/-+Lys组比较，GCDHn -/-+Lys+VE组大鼠GPx活性、CAT活性、SOD活性显著增强，GSH含量显著增加，差异有统计学意义(n P<0.05)。(3)Western blotting实验结果：与WT组比较，GCDHn -/-+Lys组和GCDHn -/-+Lys+VE组大鼠海马P38蛋白表达显著增加，差异有统计学意义(n P<0.05)；与GCDHn -/-+Lys组比较，GCDHn -/-+Lys+VE组P38蛋白表达减少，差异有统计学意义(n P<0.05)。n 结论:高赖氨酸饮食GCDHn -/-大鼠海马存在氧化应激损伤，其可能机制与激活P38启动丝裂原活化蛋白激酶信号通路有关；维生素E可降低P38表达，减轻氧化应激损伤。n “,”Objective:To investigate the mechanism of oxidative stress injury and possible pathways in glutaryl CoA dehydrogenase deficient (GCDHn -/-) rats with high lysine diet (Lys).n Methods:Four-week-old rats were randomly divided into 6 groups: wild type+standard diet group (WT, n n=6), GCDHn -/-+standard diet group (GCDHn -/-, n n=11), WT+Lys group (n n=8), GCDHn -/-+Lys group (n n=13), WT+Lys+vitamin (V) E group (n n=7), and GCDHn -/-+Lys+VE group (n n=12); rats in the WT group and GCDHn -/- group were given standard diet, and rats in the WT+Lys group, GCDHn -/-+Lys group, WT+Lys+VE group and GCDHn -/-+Lys+VE group were given high lysine diet (4.7% Lys); rats in the WT+Lys+VE and GCDHn -/-+Lys+VE group were given VE (100 mg/[kg·d]) by intragastric administration once per d, and rats in other groups were given normal saline by intragastric administration once per d. The body mass and survival of rats in each group were observed. Twenty-eight d after intervention, rats were injected intraperitoneally with 10% chloral hydrate and anesthetized; their brains were severed to obtain hippocampal tissues; and pathomorphological changes were observed by HE staining; the content/activity of glutathione peroxidase (GPx), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH) in the hippocampus were detected by ELISA; the protein expressions of P38, c-Jun N-terminal kinase (JNK) and extra-celluar regulated protein kinase (ERK) in the hippocampus were detected by Western blotting.n Results:(1) The survival ratio of rats in the GCDHn -/-+Lys group was 9/13, and that in the GCDHn -/-+Lys+VE group was 11/12. From the 7n th d of intervention, the body mass of rats in the GCDHn -/-+Lys group and GCDHn -/-+Lys+VE group was significantly lower than that in the WT group (n P<0.05). (2) As compared with that in the WT group, MDA content in hippocampal tissues of rats in the GCDHn -/-+Lys+VE group and GCDHn -/-+Lys+VE group was significantly increased (n P<0.05). As compared with WT group, GCDHn -/-+Lys group had significantly decreased GPx activity, CAT activity and SOD activity, and statistically decreased GSH content (n P<0.05). As compared with those in the GCDHn -/-+Lys+VE group, the GPx activity, CAT activity, SOD activity, and GSH content in the GCDHn -/-+Lys+VE group were significantly increased (n P<0.05). (3) Western blotting showed that as compared with that in the WT group, the P38 protein expression in the hippocampus of rats in GCDHn -/-+Lys group and GCDHn -/-+Lys+VE group was significantly increased (n P<0.05); as compared with GCDHn -/-+Lys+VE group, the P38 protein expression in the GCDHn -/-+Lys+VE group was statistically decreased (n P<0.05).n Conclusion:There is oxidative stress injury in the hippocampus of GCDHn -/- rats with Lys, whose possible mechanism is to activate P38 and initiate MAPK signaling pathway; VE protects GCDHn -/- hippocampal cells from oxidative stress by decreasing P38 expression.n