Obrenovitch T P, Richards D A
Gough-Copper Department of Neurological Surgery, Institute of Neurology, London, England.
Cerebrovasc Brain Metab Rev. 1995 Spring;7(1):1-54.
The discovery that blockade of N-methyl-D-aspartate (NMDA) receptors protects brain tissue against ischaemic damage has triggered enormous interest; and with the advance of intracerebral microdialysis, hundreds of studies have investigated changes in the extracellular levels of glutamate and other neurotransmitters during and after cerebral ischaemia. This work has made it apparent that the current concept of ischaemia-induced excitotoxicity, centred on excessive efflux of glutamate from nerve terminals, fails to correspond with reality since it conflicts with a number of key findings: (a) Excessive effluxes during ischaemia are not specific to excitatory amino acids--inhibitory transmitters are released to a similar extent; (b) neuronal death can occur several hours after a short ischaemic episode, whereas glutamate and aspartate accumulation in the neuronal microenvironment is cleared within minutes of reperfusion; (c) the penumbra is most receptive to cerebroprotection with glutamate receptor antagonists, but extracellular glutamate levels may not reach critical levels in this region; and (d) postischaemic treatment with glutamate receptor antagonists were neuroprotective in a number of studies. It has also become evident that most of the glutamate released in ischaemia is of metabolic origin, which questions the validity of therapeutic strategies aimed at preventing or reducing excessive release of neurotransmitter glutamate in ischaemia. However, the possibility that glutamate changes at the synaptic level may be small but pathologically important cannot be totally refuted. Apart from increased extracellular glutamate, the exceptional complexity of glutamate-operated ion channels can give rise to many potentially damaging mechanisms. Of particular interest are the possibilities of recurrent spreading depression in focal ischaemia, widespread and persistent strengthening of glutamatergic transmission, and abnormal modulation of the NMDA receptor-ionophore complex. There is also considerable evidence that, in certain brain regions, monoamines or their metabolic by-products may become neurotoxic either directly or from interplay with glutamatergic systems. All these processes deserve further examination to identify the most damaging and to indicate possible methods of intervention.
N-甲基-D-天冬氨酸（NMDA）受体阻滞剂可保护脑组织免受缺血性损伤这一发现引发了极大关注；随着脑内微透析技术的发展，数百项研究对脑缺血期间及之后谷氨酸及其他神经递质的细胞外水平变化进行了调查。这项工作表明，当前以神经末梢谷氨酸过度外流为核心的缺血性兴奋毒性概念与实际情况不符，因为它与一些关键发现相冲突：（a）缺血期间的过度外流并非兴奋性氨基酸所特有——抑制性递质的释放程度相似；（b）短暂缺血发作数小时后神经元会死亡，而神经元微环境中的谷氨酸和天冬氨酸积累在再灌注后几分钟内就会清除；（c）半暗带对谷氨酸受体拮抗剂的脑保护作用最为敏感，但该区域的细胞外谷氨酸水平可能未达到临界水平；（d）在多项研究中，缺血后用谷氨酸受体拮抗剂治疗具有神经保护作用。同样明显的是，缺血时释放的大部分谷氨酸来源于代谢，这对旨在预防或减少缺血时神经递质谷氨酸过度释放的治疗策略的有效性提出了质疑。然而，谷氨酸在突触水平的变化可能很小但具有病理重要性这一可能性也不能完全排除。除了细胞外谷氨酸增加外，谷氨酸操纵的离子通道异常复杂，可能引发许多潜在的损伤机制。局部缺血时反复出现的扩散性抑制、谷氨酸能传递的广泛持续增强以及NMDA受体-离子载体复合物的异常调节尤其值得关注。也有大量证据表明，在某些脑区，单胺或其代谢副产物可能直接或通过与谷氨酸能系统相互作用而产生神经毒性。所有这些过程都值得进一步研究，以确定最具破坏性的因素，并指出可能的干预方法。
