Mitochondrial Dysfunction Induced by Nuclear Poly(ADP-Ribose) Polymerase-1: a Treatable Cause of Cell Death in Stroke

被引:59
作者
Baxter, Paul [1 ,2 ]
Chen, Yanting [1 ,2 ,3 ]
Xu, Yun [3 ]
Swanson, Raymond A. [1 ,2 ]
机构
[1] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94121 USA
[2] San Francisco VA Med Ctr, Neurol Serv, San Francisco, CA 94121 USA
[3] Nanjing Univ, Sch Med, Affiliated Drum Tower Hosp, Dept Neurol, Nanjing 210008, Jiangsu, Peoples R China
基金
美国国家卫生研究院;
关键词
Ischemia; Mitochondrial depolarization; Mitochondrial permeability transition; Poly(ADP-ribose) polymerase-1; NAD(+); Apoptosis-inducing factor; FOCAL CEREBRAL-ISCHEMIA; METHYL-D-ASPARTATE; HYPOGLYCEMIC NEURONAL DEATH; TRANSIENT FOREBRAIN ISCHEMIA; PERMEABILITY TRANSITION; GAMMA-HYDROXYBUTYRATE; ARTERY OCCLUSION; RAT-BRAIN; NITRIC-OXIDE; COGNITIVE IMPAIRMENT;
D O I
10.1007/s12975-013-0283-0
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
引用
收藏
页码:136 / 144
页数:9
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