Mitochondrial dysfunction induced by nuclear poly(ADP-ribose) polymerase-1: a treatable cause of cell death in stroke.
Mitochondrial dysfunction induced by nuclear poly(ADP-ribose) polymerase-1: a treatable cause of cell death in stroke.
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DOI：
10.1007/s12975-013-0283-0
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发表时间：
2014-02
影响因子：
6.9
通讯作者：
Swanson, Raymond A.
中科院分区：
文献类型：
--
作者：
Baxter, Paul;Chen, Yanting;Xu, Yun;Swanson, Raymond A.
关键词：
许多靶向兴奋性毒性细胞死亡的药物在脑缺血动物模型中表现出强大的神经保护作用。然而，这些神经保护作用几乎普遍需要在缺血发作后以相对短的时间间隔给药。这一发现已转化为临床试验结果;针对兴奋性毒性的干预措施在缺血发作后数小时开始时没有明显的疗效，但已报告了更快开始的有益效果。因此，仍然需要在缺血后的较晚时间点进行有效的干预。在这里，我们专注于线粒体功能障碍作为一个相对较晚的缺血性神经元死亡事件和公认的原因迟发性神经元死亡。聚（ADP-核糖）聚合酶-1（PARP-1）的激活是缺血再灌注中线粒体去极化和随后的线粒体触发的细胞死亡的主要原因。PARP-1消耗胞质NAD+，从而阻断糖酵解ATP的产生和葡萄糖碳向线粒体的递送以进行氧化代谢。然而，酮体如丙酮酸盐、β-和γ-羟基丁酸盐和1，4-丁二醇可以在细胞溶质NAD+耗尽的细胞中促进线粒体代谢，只要线粒体保持功能。酮体已多次被证明在缺血动物模型中预防细胞死亡方面非常有效，但对这种方法的机会时间窗的严格研究仍有待进行。
Many drugs targeting excitotoxic cell death have demonstrated robust neuroprotective effects in animal models of cerebral ischemia. However, these neuroprotective effects have almost universally required drug administration at relatively short time intervals after ischemia onset. This finding has translated to clinical trial results; interventions targeting excitotoxicity have had no demonstrable efficacy when initiated hours after ischemia onset, but beneficial effects have been reported with more rapid initiation. Consequently, there continues to be a need for interventions with efficacy at later time points after ischemia. Here, we focus on mitochondrial dysfunction as both a relatively late event in ischemic neuronal death and a recognized cause of delayed neuronal death. Activation of poly(ADP-ribose) polymerase-1 (PARP-1) is a primary cause of mitochondrial depolarization and subsequent mitochondria-triggered cell death in ischemia reperfusion. PARP-1 consumes cytosolic NAD+, thereby blocking both glycolytic ATP production and delivery of glucose carbon to mitochondria for oxidative metabolism. However, ketone bodies such as pyruvate, beta- and gamma-hydroxybutyrate, and 1,4-butanediol can fuel mitochondrial metabolism in cells with depleted cytosolic NAD+ as long as the mitochondria remain functional. Ketone bodies have repeatedly been shown to be highly effective in preventing cell death in animal models of ischemia, but a rigorous study of the time window of opportunity for this approach remains to be performed.
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DOI：
10.1002/neu.480230915
发表时间：
1992-11-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
CHOI, DW
通讯作者：
CHOI, DW
影响因子：
7.3
作者：
DAWSON, DA;GRAHAM, DI;MACRAE, IM
通讯作者：
MACRAE, IM
DOI：
10.2741/3297
发表时间：
2009-01-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
--
作者：
David KK;Andrabi SA;Dawson TM;Dawson VL
通讯作者：
Dawson VL
DOI：
10.1073/pnas.0606526103
发表时间：
2006-11-28
影响因子：
11.1
作者：
Andrabi, Shaida A.;Kim, No Soo;Dawson, Ted M.
通讯作者：
Dawson, Ted M.
影响因子：
3.4
作者：
BERGER, NA
通讯作者：
BERGER, NA