Bai Hui-yuan, Feng Shan
Yao Xue Xue Bao. 2017 Mar;52(3):390-6.
This study was conducted to test the effects of schizandrin B (Sch B) on clozapine (CLZ) induced chronic liver injury in mice and the mechanism of action, and this may provide a new approach for clinical prevention of CLZ-induced side effects. The CLZ was given to mice for three weeks alone or co-administration with Sch B. The changes of alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and antioxidation indexes superoxide dismutase (SOD), malonic dialdehyde (MDA), glutathione (GSH) and liver histological evaluation were determined. Expression of Nrf2 was assayed in hepatic cells by immunohistochemical staining and Western blotting. The changes of relative gene expression of NAD(P)H: quinone oxidoreductase l (NQO1) and heme oxygenase 1 (HO-1) were assayed by real-time Q-PCR. The results showed that pretreatment with a lower dosage of Sch B (25, 50 mg·kg−1) prevented CLZ-induced liver injury as indicated by the reduced levels of ALT, AST and ALP, and the preserved activities of SOD, GSH and inhibiting MDA. It was shown that Sch B could up-regulate Nrf2 expression leading to nuclear accumulation of Nrf2 to induce oxidative response genes such as NQO1 and HO-1. These results suggest that Sch B could protect against liver injury induced by CLZ via the activation of the Nrf2/ARE signal pathway in a dose-dependent manner.
本研究旨在探讨五味子乙素（Sch B）对氯氮平（CLZ）诱导的小鼠慢性肝损伤的影响及其作用机制，为临床预防CLZ所致副作用提供新途径。单独或与Sch B联合给予小鼠CLZ三周。测定丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（ALP）的变化以及抗氧化指标超氧化物歧化酶（SOD）、丙二醛（MDA）、谷胱甘肽（GSH）的变化，并进行肝脏组织学评估。通过免疫组织化学染色和蛋白质印迹法检测肝细胞中Nrf2的表达。通过实时定量PCR检测NAD(P)H：醌氧化还原酶1（NQO1）和血红素加氧酶1（HO-1）相对基因表达的变化。结果表明，较低剂量（25、50 mg·kg−1）的Sch B预处理可预防CLZ诱导的肝损伤，表现为ALT、AST和ALP水平降低，SOD、GSH活性保留以及MDA受到抑制。结果显示，Sch B可上调Nrf2表达，导致Nrf2核内蓄积，从而诱导NQO1和HO-1等氧化应激反应基因。这些结果表明，Sch B可通过激活Nrf2/ARE信号通路以剂量依赖的方式保护小鼠免受CLZ诱导的肝损伤。
