EXTRACELLULAR NEUROTRANSMITTER CHANGES IN CEREBRAL-ISCHEMIA

The discovery that blockade of N-methyl-D-aspartate (NMDA) receptors p rotects brain tissue against ischaemic damage has triggered enormous i nterest; and with the advance of intracerebral microdialysis, hundreds of studies have investigated changes in the extracellular levels of g lutamate and other neurotransmitters during and after cerebral ischaem ia. This work has made it apparent that the current concept of ischaem ia-induced excitotoxicity, centred on excessive efflux of glutamate fr om nerve terminals, fails to correspond with reality since it conflict s with a number of key findings: (a) Excessive effluxes during ischaem ia 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 aspartat e accumulation in the neuronal microenvironment is cleared within minu tes of reperfusion; (c) the penumbra is most receptive to cerebroprote ction with glutamate receptor antagonists, but extracellular glutamate levels may not reach critical levels in this region; and (d) postisch aemic treatment with glutamate receptor antagonists were neuroprotecti ve in a number of studies. It has also become evident that most of the glutamate released in ischaemia is of metabolic origin, which questio ns the validity of therapeutic strategies aimed at preventing or reduc ing excessive release of neurotransmitter glutamate in ischaemia. Howe ver, 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 dam aging mechanisms. Of particular interest are the possibilities of recu rrent spreading depression in focal ischaemia, widespread and persiste nt strengthening of glutamatergic transmission, and abnormal modulatio n of the NMDA receptor-ionophore complex. There is also considerable e vidence that, in certain brain regions, monoamines or their metabolic by-products may become neurotoxic either directly or from interplay wi th glutamatergic systems. All these processes deserve further examinat ion to identify the most damaging and to indicate possible methods of intervention.