Excitatory amino acid receptors and neurodegeneration

This review describes recent advances in our understanding of the pharmacology of excitatory amino acid receptors, and the application of this knowledge to the unravelling of the aetiology of neurodegenerative diseases, and to their therapy. Ionotropic excitatory amino acid receptors can be divided into two large families, the NMDA receptor family, and the AMPA/kainate receptor family. Receptor cloning studies have shown there to be a large number of potential subtypes of receptors in both these families. Antagonists have been developed for the NMDA receptor which can interact with at least four independent drug recognition sites on the receptor. For the AMPA/kainate receptor, two classes of antagonist have so far been identified. Reasonably potent, selective and brain-penetrating antagonists now exist for virtually all these sites, and compounds inhibiting the release of glutamic acid presynaptically have also been identified, such as riluzole. The ability of glutamic acid to kill neurons (excitotoxicity) seems to be mediated, in most cases, by an interaction with NMDA receptors, leading to an uncontrollable rise in intracellular calcium concentrations and thence cell lysis and death. The setting-up of glutamatergic loops seems to be a key process in the maintenance, spread and amplification of neurodegenerative foci. The existence of such processes has been amply demonstrated in animal models of stroke, in which both NMDA and AMPA/kainate receptor antagonists have neuroprotective effects. Clinical trials are underway with NMDA receptor antagonists in stroke. Excitotoxic mechanisms probably also contribute to pathology in head trauma and viral encephalopathy. Ingestion of excitatory amino acids may play a role in neurological conditions of dietary aetiology, such as neurolathyrism and domoic acid intoxication. For chronic neurodegenerative diseases, the role of excitatory amino acids is much less clear, although there is some evidence for the existence of excitotoxic mechanisms in amyotrophic lateral sclerosis. Evidence from animal models suggests that drugs that block glutamatergic neurotransmission might be beneficial in Parkinson's disease, Huntington's chorea and amyotrophic lateral sclerosis, but the relevance of these animal models to the human pathology is not clear. However, preliminary clinical results suggest riluzole to be efficacious in prolonging survival in amyotrophic lateral sclerosis, and certain weak NMDA receptor antagonists are currently used in the treatment of Parkinson's disease. The next few years could witness a breakthrough in the treatment of neurological conditions as drugs that interfere with glutamatergic transmission become available for clinical use.