期刊
EUROPEAN JOURNAL OF NEUROSCIENCE
卷 24, 期 8, 页码 2169-2176出版社
WILEY
DOI: 10.1111/j.1460-9568.2006.05110.x
关键词
global ischemia; mouse; neuroprotection; nicotinamide
资金
- NIDDK NIH HHS [R01 DK073446, DK 073446] Funding Source: Medline
- NINDS NIH HHS [NS 030337, R01 NS030337] Funding Source: Medline
Zinc neurotoxicity has been demonstrated in ischemic, seizure, hypoglycemic, and trauma-induced neuronal death where Zn2+ is thought to be synaptically released and taken up in neighbouring neurons, reaching toxic concentrations. We previously demonstrated that toxicity of extracellular Zn2+ depended on entry, elevation in intracellular free Zn2+ ([Zn2+](i)), a reduction in NAD(+) and ATP levels, and dysfunction of glycolysis and cellular metabolism. We suggested that PARP-1 activation alone can not explain this loss of neuronal NAD(+). NAD(+) was recently demonstrated to permeate neurons and glia, and we have now shown that exogenous NAD(+) can reduce Zn2+ neurotoxicity, and 3-acetylpyridine, which generates inactive NAD(+), potentiated Zn2+ neurotoxicity. Sirtinol and 2-hydroxynaphthaldehyde, inhibitors of the sirtuin pathway (SIRT proteins are NAD(+)-catabolic protein deacetylases), attenuated both acute and chronic Zn2+ neurotoxicity. Resveratrol and fisetin (sirtuin activators) potentiated NAD(+) loss and Zn2+ neurotoxicities. Furthermore, neuronal cultures derived from the Wld(s) mouse, which overexpress the NAD(+) synthetic enzyme nicotinamide mononucleotide adenyl transferase (NMNAT-1), had reduced sensitivity to Zn2+ neurotoxicity. Finally, nicotinamide was demonstrated to attenuate CA1 neuronal death after 10 min of global ischemia in rat even if administered 1 h after the insult. Together with previous data, these results further implicate NAD(+) levels in Zn2+ neurotoxicity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据