Mechanism of oxidative stress injury in the hippocampus of glutaryl CoA dehydrogenase -/- rats / 中华神经医学杂志

ABSTRACT

Objective:To investigate the mechanism of oxidative stress injury and possible pathways in glutaryl CoA dehydrogenase deficient (GCDH -/-) rats with high lysine diet (Lys). Methods:Four-week-old rats were randomly divided into 6 groups: wild type+standard diet group (WT, n=6), GCDH -/-+standard diet group (GCDH -/-, n=11), WT+Lys group ( n=8), GCDH -/-+Lys group ( n=13), WT+Lys+vitamin (V) E group ( n=7), and GCDH -/-+Lys+VE group ( n=12); rats in the WT group and GCDH -/- group were given standard diet, and rats in the WT+Lys group, GCDH -/-+Lys group, WT+Lys+VE group and GCDH -/-+Lys+VE group were given high lysine diet (4.7% Lys); rats in the WT+Lys+VE and GCDH -/-+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. Results:(1) The survival ratio of rats in the GCDH -/-+Lys group was 9/13, and that in the GCDH -/-+Lys+VE group was 11/12. From the 7 th d of intervention, the body mass of rats in the GCDH -/-+Lys group and GCDH -/-+Lys+VE group was significantly lower than that in the WT group ( P<0.05). (2) As compared with that in the WT group, MDA content in hippocampal tissues of rats in the GCDH -/-+Lys+VE group and GCDH -/-+Lys+VE group was significantly increased ( P<0.05). As compared with WT group, GCDH -/-+Lys group had significantly decreased GPx activity, CAT activity and SOD activity, and statistically decreased GSH content ( P<0.05). As compared with those in the GCDH -/-+Lys+VE group, the GPx activity, CAT activity, SOD activity, and GSH content in the GCDH -/-+Lys+VE group were significantly increased ( 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 GCDH -/-+Lys group and GCDH -/-+Lys+VE group was significantly increased ( P<0.05); as compared with GCDH -/-+Lys+VE group, the P38 protein expression in the GCDH -/-+Lys+VE group was statistically decreased ( P<0.05). Conclusion:There is oxidative stress injury in the hippocampus of GCDH -/- rats with Lys, whose possible mechanism is to activate P38 and initiate MAPK signaling pathway; VE protects GCDH -/- hippocampal cells from oxidative stress by decreasing P38 expression.