Suh Sang Won, Hamby Aaron M, Gum Elizabeth T, Shin Byung Seop, Won Seok Joon, Sheline Christian T, Chan Pak H, Swanson Raymond A
Department of Neurology, Veterans Affairs Medical Center, University of California, San Francisco, California 94121, USA.
J Cereb Blood Flow Metab. 2008 Oct;28(10):1697-706. doi: 10.1038/jcbfm.2008.61. Epub 2008 Jun 11.
Oxidative stress and zinc release are both known to contribute to neuronal death after hypoglycemia; however, the cause-effect relationships between these events are not established. Here we found, using a rat model of profound hypoglycemia, that the neuronal zinc release and translocation that occur immediately after hypoglycemia are prevented by the nitric oxide synthase inhibitor 7-nitroindazole but not by overexpression of superoxide dismutase-1 (SOD-1). However, overexpression of SOD-1 prevented activation of poly(ADP-ribose) polymerase-1 (PARP-1) and neuronal death, suggesting that zinc release is upstream of superoxide production. Accordingly, zinc-induced superoxide production was blocked in neuronal cultures by the NADPH oxidase inhibitor apocynin and by genetic deficiency in the p47(phox) subunit of NADPH oxidase. A key role for the vesicular zinc pool in this process was suggested by reduced superoxide formation and neuronal death in mice deficient in zinc transporter 3. Together, these findings suggest a series of events in which nitric oxide production triggers vesicular zinc release, which in turn activates NADPH oxidase and PARP-1. This sequence may also occur in other central nervous system disorders in which zinc, nitric oxide, and oxidative stress have been linked.
氧化应激和锌释放均被认为与低血糖后的神经元死亡有关；然而，这些事件之间的因果关系尚未确立。在这里，我们使用深度低血糖大鼠模型发现，低血糖后立即发生的神经元锌释放和易位可被一氧化氮合酶抑制剂7-硝基吲唑阻止，但超氧化物歧化酶-1（SOD-1）的过表达则不能。然而，SOD-1的过表达可防止聚（ADP-核糖）聚合酶-1（PARP-1）的激活和神经元死亡，这表明锌释放是超氧化物产生的上游事件。因此，锌诱导的超氧化物产生在神经元培养物中被NADPH氧化酶抑制剂阿朴吗啡和NADPH氧化酶p47（phox）亚基的基因缺陷所阻断。锌转运体3缺陷小鼠中超氧化物形成减少和神经元死亡提示了囊泡锌池在这一过程中的关键作用。总之，这些发现提示了一系列事件，其中一氧化氮的产生触发囊泡锌释放，进而激活NADPH氧化酶和PARP-1。这一序列也可能发生在锌、一氧化氮和氧化应激相关的其他中枢神经系统疾病中。
