Bolaños J P, Almeida A
Departamento de Bioquímica y Biología Molecular, Universidad de Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
Biochim Biophys Acta. 1999 May 5;1411(2-3):415-36. doi: 10.1016/s0005-2728(99)00030-4.
A large body of evidence has appeared over the last 6 years suggesting that nitric oxide biosynthesis is a key factor in the pathophysiological response of the brain to hypoxia-ischemia. Whilst studies on the influence of nitric oxide in this phenomenon initially offered conflicting conclusions, the use of better biochemical tools, such as selective inhibition of nitric oxide synthase (NOS) isoforms or transgenic animals, is progressively clarifying the precise role of nitric oxide in brain ischemia. Brain ischemia triggers a cascade of events, possibly mediated by excitatory amino acids, yielding the activation of the Ca2+-dependent NOS isoforms, i.e. neuronal NOS (nNOS) and endothelial NOS (eNOS). However, whereas the selective inhibition of nNOS is neuroprotective, selective inhibition of eNOS is neurotoxic. Furthermore, mainly in glial cells, delayed ischemia or reperfusion after an ischemic episode induces the expression of Ca2+-independent inducible NOS (iNOS), and its selective inhibition is neuroprotective. In conclusion, it appears that activation of nNOS or induction of iNOS mediates ischemic brain damage, possibly by mitochondrial dysfunction and energy depletion. However, there is a simultaneous compensatory response through eNOS activation within the endothelium of blood vessels, which mediates vasodilation and hence increases blood flow to the damaged brain area.
在过去6年里，大量证据表明一氧化氮生物合成是大脑对缺氧缺血病理生理反应的关键因素。虽然最初关于一氧化氮在此现象中影响的研究得出了相互矛盾的结论，但使用更好的生化工具，如选择性抑制一氧化氮合酶（NOS）同工型或转基因动物，正在逐步阐明一氧化氮在脑缺血中的精确作用。脑缺血引发一系列事件，可能由兴奋性氨基酸介导，导致钙依赖性NOS同工型即神经元型NOS（nNOS）和内皮型NOS（eNOS）的激活。然而，虽然对nNOS的选择性抑制具有神经保护作用，但对eNOS的选择性抑制却是神经毒性的。此外，主要在胶质细胞中，缺血发作后的延迟缺血或再灌注会诱导钙非依赖性诱导型NOS（iNOS）的表达，其选择性抑制具有神经保护作用。总之，似乎nNOS的激活或iNOS的诱导介导了缺血性脑损伤，可能是通过线粒体功能障碍和能量耗竭。然而，血管内皮内通过eNOS激活会同时产生一种代偿反应，介导血管舒张，从而增加流向受损脑区的血流量。
