The pharmacological manipulation of glutamate receptors and neuroprotection

ABSTRACT

The overactivation of glutamate receptors is a major cause of Ca2+ overload in cells, potentially leading to cell damage and death. There is an abundance of agents and mechanisms by which glutamate receptor activation can be prevented or modulated in order to control these effects. They include the well-established, competitive and non-competitive antagonists at the N-methyl-D-aspartate (NMDA) receptors and modulators of desensitisation of the  -amino-3-hydroxy-5-mmethyl-4-isoxazole-propionic acid (AMP) receptors. More recently, it has emerged that some compounds can acrt selectively at different subnuits of glutamate receptors,allowing a different blockade of subtypes. It is also becoming clear that a number of endogenous compounds, including purines, can modify glutamate receptor senistivity. The kynurenine pathway is an alternative but distinct pathway to the generation glutamate receptor ligands. The products of tryptophan metablism via kynurenine pathway include both quinolinic acid, a selective agonist at several glutamate receptor subtypes. The levels of these metabolites change as a result of the activation of inflammatory processes and immune-competent cells, and may have a significant impact on Ca2+ fluxes and neuronal damage. Drugs which target some of these various sites and processes, or which change the balance between the excitotoxin quinolinic acid and the neuroprotective kynurenic acid, could also have potential as neuroprotective drugs (AU)