脑缺血时细胞外神经递质改变。

T P Obrenovitch, D A Richards
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引用次数: 0

摘要

n -甲基- d -天冬氨酸(NMDA)受体阻断可保护脑组织免受缺血损伤的发现引起了极大的兴趣;随着脑内微透析技术的发展,数百项研究已经研究了脑缺血期间和之后谷氨酸和其他神经递质细胞外水平的变化。这项工作表明,目前以谷氨酸从神经末梢过度外排为中心的缺血诱导兴奋性毒性的概念与现实不符,因为它与许多关键发现相冲突:(a)缺血期间的过度外排并非特定于兴奋性氨基酸-抑制性递质释放到类似程度;(b)神经元死亡可在短暂缺血发作后数小时发生,而谷氨酸和天冬氨酸在神经元微环境中的积累在再灌注后数分钟内被清除;(c)半暗带最容易接受谷氨酸受体拮抗剂的脑保护,但该区域的细胞外谷氨酸水平可能未达到临界水平;(d)在一些研究中,用谷氨酸受体拮抗剂治疗脑缺血后具有神经保护作用。很明显,大多数在缺血中释放的谷氨酸是代谢性的,这对旨在防止或减少在缺血中过度释放神经递质谷氨酸的治疗策略的有效性提出了质疑。然而,谷氨酸在突触水平发生变化的可能性可能很小,但在病理上很重要,这一点不能完全否定。除了增加细胞外谷氨酸外,谷氨酸操作的离子通道的异常复杂性可以引起许多潜在的破坏性机制。特别令人感兴趣的是局灶性缺血复发性播散性抑郁的可能性,谷氨酸能传递的广泛和持续加强,以及NMDA受体-离子载体复合物的异常调节。也有相当多的证据表明,在某些大脑区域,单胺或其代谢副产物可能直接或通过与谷氨酸系统相互作用而具有神经毒性。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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Extracellular neurotransmitter changes in cerebral ischaemia.

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.

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