Strijbos P J
Department of Molecular Neurobiology Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park-North, Harlow, Essex, United Kingdom.
Crit Rev Neurobiol. 1998;12(3):223-43. doi: 10.1615/critrevneurobiol.v12.i3.40.
The observation that the free radical nitric oxide (NO) acts as a cell signaling molecule in key physiological processes such as regulation of blood pressure and immunological host-defense responses is probably one of the most important and exciting findings made in biology in the last decade. Likewise, in the brain NO has been implicated in a number of fundamental processes, including memory formation, sexual behavior and the control of cerebral blood flow. This has radically altered the accepted dogma of brain physiology and has placed NO at the center stage of neuroscience research. Evidence suggests that some of the actions of NO in the brain may be intimately linked to those of the classic excitatory neurotransmitter glutamate. The historical view that aberrations in glutamate signal transduction may underlie central neurodegeneration following, for example, cerebral ischemia, has implicated NO, by default, as a potential mediator of neuronal death. Indeed, with the advent of potent and specific compounds that interact with NO synthesizing (NOS) enzymes and with the NO signaling cascade, there is now ample evidence to suggest that NO can mediate neurodegeneration, although its involvement is paradoxical. Its cerebrovascular effects may act to limit ischemic damage by preserving tissue perfusion and preventing platelet aggregation, while NO produced in the parenchyma, either directly following the ischemic insult or at a later stage as part of a neuroinflammatory response, may be deleterious to the outcome of ischemia. Nonetheless, significant efforts are made into the potential therapeutic use of chemical NO donors and specific NOS inhibitors in the treatment of cerebral ischemia and other central neurodegenerative disorders. Here, the latest concepts and developments in our understanding of the role of NO in cerebral ischemic neurodegeneration are discussed.
自由基一氧化氮（NO）在诸如血压调节和免疫宿主防御反应等关键生理过程中作为细胞信号分子发挥作用，这一发现可能是过去十年生物学领域最重要且最令人兴奋的发现之一。同样，在大脑中，NO也参与了许多基本过程，包括记忆形成、性行为和脑血流量控制。这从根本上改变了人们对脑生理学的既有认知，并使NO成为神经科学研究的核心。有证据表明，NO在大脑中的一些作用可能与经典兴奋性神经递质谷氨酸的作用密切相关。历史观点认为，例如脑缺血后谷氨酸信号转导异常可能是中枢神经退行性变的基础，默认情况下，这也将NO牵连为神经元死亡的潜在介质。事实上，随着与NO合成（NOS）酶及NO信号级联相互作用的强效特异性化合物的出现，现在有充分证据表明NO可介导神经退行性变，尽管其参与情况较为复杂。它的脑血管效应可能通过维持组织灌注和防止血小板聚集来限制缺血损伤，而实质内产生的NO，无论是在缺血损伤后直接产生，还是在后期作为神经炎症反应的一部分产生，都可能对缺血结局有害。尽管如此，人们仍在大力研究化学NO供体和特异性NOS抑制剂在治疗脑缺血及其他中枢神经退行性疾病方面的潜在治疗用途。在此，将讨论我们对NO在脑缺血性神经退行性变中作用的最新认识和进展。
