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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Apoptosis-inducing factor triggered by poly(ADP-Ribose) polymerase and bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia.
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Apoptosis-inducing factor triggered by poly(ADP-Ribose) polymerase and bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia.

机译：聚（ADP-核糖）聚合酶触发的凋亡诱导因子和bid介导氧葡萄糖剥夺和局灶性脑缺血后神经元细胞死亡。

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摘要

Delayed neuronal cell death occurring hours after reperfusion is a hallmark of ischemic stroke and a primary target for neuroprotective strategies. In the present study, we investigated whether apoptosis-inducing factor (AIF), a caspase-independent proapoptotic protein, is responsible for neuronal cell death after glutamate toxicity and oxygen-glucose deprivation (OGD) in vitro and after experimental stroke in vivo. AIF translocated to the nucleus in which it colocalized with DNA fragmentation and nuclear apoptotic morphology after exposure to glutamate or OGD in cultured neurons or after transient middle cerebral artery occlusion (MCAo) in mice. Small inhibitory RNA-mediated downregulation of AIF reduced glutamate- and OGD-induced neuronal apoptosis by 37 and 60%, respectively (p < 0.01). Moreover, Harlequin mutant mice, which express AIF at low levels (approximately 20% of wild-type mice), displayed smaller infarct volumes (-43%; p < 0.03) and showed dramatically reduced cell death in the ischemic penumbra after 45 min of MCAo compared with wild-type littermates. Inhibition of poly(ADP-ribose) polymerase and Bid reduced nuclear AIF translocation. These results provide the first evidence for a causal role of AIF in ischemic neuronal cell death. Therefore, caspase-independent cell death signaling may provide a promising novel target for therapeutic interventions in cerebrovascular diseases.
机译：再灌注后数小时发生的神经元细胞延迟死亡是缺血性中风的标志，也是神经保护策略的主要靶标。在本研究中，我们调查了体外和实验性中风后谷氨酸毒性和氧葡萄糖剥夺（OGD）后神经元细胞死亡是否是凋亡诱导因子（AIF），一种不依赖caspase的促凋亡蛋白。在培养的神经元中暴露于谷氨酸或OGD后或在小鼠中短暂性中脑动脉闭塞（MCAo）后，AIF易位至细胞核，并与DNA片段化和核凋亡形态共同定位。小抑制性RNA介导的AIF下调分别降低了谷氨酸和OGD诱导的神经元凋亡37％和60％（p <0.01）。此外，以低水平表达AIF的Harlequin突变小鼠（约占野生型小鼠的20％）显示出较小的梗塞体积（-43％; p <0.03），并且在缺血半影后45分钟后细胞死亡显着减少。 MCAo与野生型同窝仔相比。聚（ADP-核糖）聚合酶和出价的抑制减少了核AIF易位。这些结果为AIF在缺血性神经元细胞死亡中起因作用提供了第一个证据。因此，不依赖胱天蛋白酶的细胞死亡信号传导可能为脑血管疾病的治疗干预提供有希望的新靶标。

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