Zhu C, Wang X, Huang Z, Qiu L, Xu F, Vahsen N, Nilsson M, Eriksson P S, Hagberg H, Culmsee C, Plesnila N, Kroemer G, Blomgren K
Institute of Neuroscience and Physiology, Göteborg University, Göteborg, Sweden.
Cell Death Differ. 2007 Apr;14(4):775-84. doi: 10.1038/sj.cdd.4402053. Epub 2006 Oct 13.
Nine-day-old harlequin (Hq) mice carrying the hypomorphic apoptosis-inducing factor (AIF)(Hq) mutation expressed 60% less AIF, 18% less respiratory chain complex I and 30% less catalase than their wild-type (Wt) littermates. Compared with Wt, the infarct volume after hypoxia-ischemia (HI) was reduced by 53 and 43% in male (YX(Hq)) and female (X(Hq)X(Hq)) mice, respectively (P<0.001). The Hq mutation did not inhibit HI-induced mitochondrial release of cytochrome c or activation of calpain and caspase-3. The broad-spectrum caspase inhibitor quinoline-Val-Asp(OMe)-CH(2)-PH (Q-VD-OPh) decreased the activation of all detectable caspases after HI, both in Wt and Hq mice. Q-VD-OPh reduced the infarct volume equally in Hq and in Wt mice, and the combination of Hq mutation and Q-VD-OPh treatment showed an additive neuroprotective effect. Oxidative stress leading to nitrosylation and lipid peroxidation was more pronounced in ischemic brain areas from Hq than Wt mice. The antioxidant edaravone decreased oxidative stress in damaged brains, more pronounced in the Hq mice, and further reduced brain injury in Hq but not in Wt mice. Thus, two distinct strategies can enhance the neuroprotection conferred by the Hq mutation, antioxidants, presumably compensating for a defect in AIF-dependent redox detoxification, and caspase inhibitors, presumably interrupting a parallel pathway leading to cellular demise.
携带低表达凋亡诱导因子（AIF）（Hq）突变的9日龄丑角（Hq）小鼠，其AIF表达量比野生型（Wt）同窝小鼠少60%，呼吸链复合体I少18%，过氧化氢酶少30%。与Wt相比，雄性（YX（Hq））和雌性（X（Hq）X（Hq））小鼠缺氧缺血（HI）后的梗死体积分别减少了53%和43%（P<0.001）。Hq突变并未抑制HI诱导的细胞色素c从线粒体释放或钙蛋白酶和半胱天冬酶-3的激活。广谱半胱天冬酶抑制剂喹啉-缬氨酸-天冬氨酸（OMe）-CH₂-PH（Q-VD-OPh）可降低HI后Wt和Hq小鼠中所有可检测到的半胱天冬酶的激活。Q-VD-OPh在Hq和Wt小鼠中同等程度地减少梗死体积，Hq突变与Q-VD-OPh治疗联合显示出相加的神经保护作用。与Wt小鼠相比，Hq小鼠缺血脑区中导致亚硝基化和脂质过氧化的氧化应激更为明显。抗氧化剂依达拉奉可降低受损脑内的氧化应激，在Hq小鼠中更明显，并进一步减轻Hq小鼠而非Wt小鼠的脑损伤。因此，两种不同的策略可增强Hq突变赋予的神经保护作用，抗氧化剂大概是补偿AIF依赖性氧化还原解毒缺陷，而半胱天冬酶抑制剂大概是中断导致细胞死亡的平行途径。
