Brennan-Minnella Angela M, Won Seok Joon, Swanson Raymond A
1 Department of Neurology, University of California San Francisco , San Francisco, California.
Antioxid Redox Signal. 2015 Jan 10;22(2):161-74. doi: 10.1089/ars.2013.5767.
Neuronal superoxide production contributes to cell death in both glutamate excitotoxicity and brain ischemia (stroke). NADPH oxidase-2 (NOX2) is the major source of neuronal superoxide production in these settings, and regulation of NOX2 activity can thereby influence outcome in stroke.
Reduced NOX2 activity can rescue cells from oxidative stress and cell death that otherwise occur in excitotoxicity and ischemia. NOX2 activity is regulated by several factors previously shown to affect outcome in stroke, including glucose availability, intracellular pH, protein kinase ζ/δ, casein kinase 2, phosphoinositide-3-kinase, Rac1/2, and phospholipase A2. The newly identified functions of these factors as regulators of NOX2 activity suggest alternative mechanisms for their effects on ischemic brain injury.
Key aspects of these regulatory influences remain unresolved, including the mechanisms by which rac1 and phospholipase activities are coupled to N-methyl-D-aspartate (NMDA) receptors, and whether superoxide production by NOX2 triggers subsequent superoxide production by mitochondria.
It will be important to establish whether interventions targeting the signaling pathways linking NMDA receptors to NOX2 in brain ischemia can provide a greater neuroprotective efficacy or a longer time window to treatment than provided by NMDA receptor blockade alone. It will likewise be important to determine whether dissociating superoxide production from the other signaling events initiated by NMDA receptors can mitigate the deleterious effects of NMDA receptor blockade.
在谷氨酸兴奋性毒性和脑缺血（中风）中，神经元超氧化物的产生均会导致细胞死亡。NADPH氧化酶-2（NOX2）是这些情况下神经元超氧化物产生的主要来源，因此对NOX2活性的调节会影响中风的预后。
降低NOX2活性可使细胞免受氧化应激以及在兴奋性毒性和缺血中原本会发生的细胞死亡。NOX2活性受多种先前已证明会影响中风预后的因素调节，包括葡萄糖可用性、细胞内pH值、蛋白激酶ζ/δ、酪蛋白激酶2、磷酸肌醇-3-激酶、Rac1/2和磷脂酶A2。这些因素作为NOX2活性调节剂的新确定功能提示了它们对缺血性脑损伤产生影响的替代机制。
这些调节影响的关键方面仍未解决，包括Rac1和磷脂酶活性与N-甲基-D-天冬氨酸（NMDA）受体偶联的机制，以及NOX2产生的超氧化物是否会触发线粒体随后产生超氧化物。
确定针对脑缺血中连接NMDA受体与NOX2的信号通路的干预措施是否能比单独阻断NMDA受体提供更大的神经保护功效或更长的治疗时间窗非常重要。同样重要的是确定将超氧化物产生与由NMDA受体引发的其他信号事件分离是否可以减轻NMDA受体阻断的有害影响。
