Glutamate receptor antagonists in cerebral ischaemia

Glutamate mediated neuronal death has been implicated in every human neurodegenerative disease, but cerebral ischaemia is the area where the modulation of excitotoxicity is closest to providing a new therapeutic avenue. In cerebral ischaemia there is a marked, immediate increase in the extracellular concentration of glutamate, irrespective of the nature and primary cause of the ischaemic episode. Elevations in the extracellular concentrations of glutamate lead to excessive activation of the glutamate NMDA and AMPA receptor subtypes initiating a sequence of neurochemical events which lead ultimately to neuronal death. Animal models of focal cerebral ischaemia have been particularly influential in defining the anti-ischaemic effects of agents which block NMDA or AMPA receptors or which putatively reduce glutamate release. The systemic generation of anti-ischaemic efficacy data which addresses every contentious issue has been crucial for the progression of these agents to man.