Involvement of poly ADP ribosyl polymerase-1 in acute but not chronic zinc toxicity

被引:31
作者
Sheline, CT
Wang, HM
Cai, AL
Dawson, VL
Choi, DW
机构
[1] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA
[2] Washington Univ, Sch Med, Ctr Study Nervous Syst Injury, St Louis, MO 63110 USA
[3] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA
[4] Johns Hopkins Univ, Dept Neurosci & Physiol, Inst Cell Engn, Baltimore, MD 21287 USA
关键词
astrocyte; ATP; mouse; NAD(+);
D O I
10.1046/j.1460-9568.2003.02865.x
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
We have previously suggested that zinc-induced neuronal death may be mediated in part by inhibition of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), secondary to depletion of the essential cosubstrate NAD(+). Given convergent evidence implicating the NAD(+)-catabolizing enzyme, poly ADP ribosyl polymerase (PARP) in mediating ATP depletion and neuronal death after excitotoxic and ischemic insults, we tested the specific hypothesis that the neuronal death induced by exposure to toxic levels of extracellular zinc might be partly mediated by PARP PARP was activated in cultured mouse cortical astrocytes after a toxic acute Zn2+ exposure (350 muM Zn2+ for 15 min), but not in cortical neurons or glia after exposure to a toxic chronic Zn2+ exposure (40 muM Zn2+ for 1-4h), an exposure sufficient to deplete NAD(+) and ATP levels. Furthermore, the neurotoxicity induced by acute, but not chronic, Zn2+ exposure was reduced in mixed neuronal-glial cultures prepared from mutant mice lacking the PARP gene. These data suggest PARP activation may contribute to more fulminant forms of Zn2+-induced neuronal death.
引用
收藏
页码:1402 / 1409
页数:8
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