EDARAVONE PREVENTS FAS-INDUCED FULMINANT HEPATIC FAILURE IN MICE BY REGULATING MITOCHONDRIAL BCL-XL AND BAX
EDARAVONE PREVENTS FAS-INDUCED FULMINANT HEPATIC FAILURE IN MICE BY REGULATING MITOCHONDRIAL BCL-XL AND BAX
复制标题
依达拉奉通过调节线粒体 BCL-XL 和 BAX 预防 FAS 诱导的小鼠暴发性肝衰竭
作者：
Takeshi Miyasou;A. Kwon;Katsushige Tsuji;Z. Qiu;T. Okumura;Y. Kamiyama
暴发性肝功能衰竭是一种严重的疾病，除非进行肝移植，否则治愈率很低。依达拉奉是一种自由基清除剂，已被批准用于治疗急性脑梗死，其作用机制涉及清除缺血组织中产生的自由基。我们评估了3-甲基-1-苯基-2-吡唑啉-5-酮（依达拉奉）预防Fas诱导的小鼠急性肝衰竭的能力，并研究了观察到的作用的机制。BALB/c小鼠以0.25g/g（i. v.）纯化的仓鼠激动剂抗Fas单克隆抗体（克隆Jo 2）的体重。小鼠在Jo 2治疗之前或之后还接受依达拉奉或等渗氯化钠溶液。依达拉奉能明显提高小鼠的存活率。组织病理学检查和血清天门冬氨酸氨基转移酶水平表明，依达拉奉可减轻Jo 2引起的肝损伤程度。末端脱氧核苷酸转移酶介导的2-脱氧尿苷5-三磷酸缺口末端标记染色显示依达拉奉减少了凋亡肝细胞的数量。依达拉奉还阻止细胞色素c释放和半胱天冬酶3活性，这被认为是线粒体破坏后细胞凋亡的标志物。因此，我们认为依达拉奉的抗凋亡活性涉及阻断Fas诱导的凋亡中的信号转导通路。线粒体Bcl-xL和Bax在线粒体膜中形成通道，并通过它们的平衡调节其渗透性，参与线粒体破坏。Western blotting显示依达拉奉组Bcl-xL-Bax比值明显高于对照组。依达拉奉可能通过调节线粒体Bcl-xL和Bax的表达，保护Fas诱导的肝细胞凋亡。
Fulminant hepatic failure is a serious disease that has a poor cure rate unless liver transplantation is performed. Edaravone, a free radical scavenger, has been approved for the treatment of acute cerebral infarction, and its mechanism of action involves scavenging free radicals generated in ischemic tissues. We assessed the ability of 3-methyl-1-phenyl-2-pyrazolim-5-one (edaravone) to prevent Fas-induced acute liver failure in mice and examined the mechanisms underlying the observed effects. BALB/c mice were administered 0.25 &mgr;g/g (i.v.) body weight of a purified hamster agonist anti-Fas monoclonal antibody (clone Jo2). The mice also received either edaravone or isotonic sodium chloride solution before or after Jo2 treatment. Edaravone improved the survival rate of the mice markedly. Histopathological findings and serum aspartate aminotransferase levels showed that edaravone reduced the degree of liver injury caused by Jo2. Terminal deoxynucleotidyl transferase-mediated 2&vprime;-deoxyuridine 5&vprime;-triphosphate nick end labeling staining showed that edaravone reduced the number of apoptotic hepatocytes. Edaravone also prevented cytochrome c release and caspase 3 activity, recognized as markers of apoptosis after mitochondrial disruption. Therefore, we considered that the antiapoptotic activity of edaravone involved blocking signals in the mitochondria-dependent pathway of Fas-induced apoptosis. Mitochondrial Bcl-xL and Bax, which form a channel in the mitochondrial membrane and, by their balance, regulate its permeability, are involved in mitochondrial disruption. Western blotting showed that the Bcl-xL-Bax ratio of the edaravone group was much higher than that of the control group. In conclusion, edaravone might protect hepatocytes from Fas-induced mitochondria-dependent apoptosis by regulating mitochondrial Bcl-xL and Bax.