Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase
Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase
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DOI：
10.1172/jci30077
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发表时间：
2007-04-01
影响因子：
15.9
通讯作者：
Swanson, Raymond A.
中科院分区：
文献类型：
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作者：
Suh, Sang Won;Gum, Elizabeth T.;Swanson, Raymond A.
低血糖昏迷和脑损伤是胰岛素治疗的潜在并发症。海马和大脑皮层中的某些神经元特别容易受到低血糖细胞死亡的影响，氧化应激是这种细胞死亡过程中的关键事件。在这里，我们表明，低血糖诱导的氧化应激和神经元死亡主要归因于葡萄糖再灌注过程中神经元NADPH氧化酶的激活。NADPH氧化酶抑制剂夹竹桃苷在细胞培养和体内胰岛素诱导的低血糖模型中阻断了超氧化物的产生和神经元死亡。在使用小鼠或培养的NADPH氧化酶p47（phox）亚基缺陷的神经元的研究中，超氧化物产生和神经元死亡也被阻断。螯合锌与EDTA二钠钙阻止组装的神经元NADPH氧化酶复合物和超氧化物的产生。抑制己糖一磷酸分流，利用葡萄糖再生NADPH，也防止超氧化物的形成和神经元死亡，这表明一种机制连接葡萄糖再灌注超氧化物的形成。此外，在再灌注期间，超氧化物产生和神经元死亡的程度随着葡萄糖浓度的增加而增加。这些结果表明，低血糖昏迷后的高血糖浓度可以通过涉及细胞外锌释放和神经元NADPH氧化酶激活的机制启动神经元死亡。
Hypoglycemic coma and brain injury are potential complications of insulin therapy. Certain neurons in the hippocampus and cerebral cortex are uniquely vulnerable to hypoglycemic cell death, and oxidative stress is a key event in this cell death process. Here we show that hypoglycemia-induced oxidative stress and neuronal death are attributable primarily to the activation of neuronal NADPH oxidase during glucose reperfusion. Superoxide production and neuronal death were blocked by the NADPH oxidase inhibitor apocynin in both cell culture and in vivo models of insulin-induced hypoglycemia. Superoxide production and neuronal death were also blocked in studies using mice or cultured neurons deficient in the p47(phox) subunit of NADPH oxidase. Chelation of zinc with calcium disodium EDTA blocked both the assembly of the neuronal NADPH oxidase complex and superoxide production. Inhibition of the hexose monophosphate shunt, which utilizes glucose to regenerate NADPH, also prevented superoxide formation and neuronal death, suggesting a mechanism linking glucose reperfusion to superoxide formation. Moreover, the degree of superoxide production and neuronal death increased with increasing glucose concentrations during the reperfusion period. These results suggest that high blood glucose concentrations following hypoglycemic coma can initiate neuronal death by a mechanism involving extracellular zinc release and activation of neuronal NADPH oxidase.