EXCITATORY AMINO-ACID RECEPTORS AND NEURODEGENERATION

This review describes recent advances in our understanding of the phar macology of excitatory amino acid receptors, and the application of th is knowledge to the unravelling of the aetiology of neurodegenerative diseases, and to their therapy. Ionotropic excitatory amino acid recep tors can be divided into two large families, the NMDA receptor family, and the AMPA/kainate receptor family. Receptor cloning studies have s hown there to be a large number of potential subtVpes of receptors in both these families. Antagonists have been developed for the NMDA rece ptor which can interact with at least four independent drug recognitio n 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 si tes, and compounds inhibiting the release of glutamic acid presynaptic ally have also been identified, such as riluzole. The ability of gluta mic acid to kill neurons (excitotoxicity) seems to be mediated, in mos t cases, by an interaction with NMDA receptors, leading to an uncontro llable rise in intracellular calcium concentrations and thence cell ly sis and death. The setting-up of glutamatergic loops seems to be a key process in the maintenance, spread and amplification of neurodegenera tive foci. The existence of such processes has been amply demonstrated in animal models of stroke, in which both NMDA and AMPA/kainate recep tor antagonists have neuroprotective effects. Clinical trials are unde rway with NMDA receptor antagonists in stroke. Excitotoxic mechanisms probably also contribute to pathology in head trauma and viral encepha lopathy. Ingestion of excitatory amino acids may play a role in neurol ogical conditions of dietary aetiology, such as neurolathyrism and dom oic acid intoxication. For chronic neurodegenerative diseases, the rol e of excitatory amino acids is much less clear, although there is some evidence for the existence of excitotoxic mechanisms in amyotrophic l ateral sclerosis. Evidence from animal models suggests that drugs that block glutamatergic neurotransmission might be beneficial in Parkinso n's disease, Huntington's chorea and amyotrophic lateral sclerosis, bu t the relevance of these animal models to the human pathology is not c lear. However, preliminary clinical results suggest riluzole to be eff icacious in prolonging survival in amyotrophic lateral sclerosis, and certain weak NMDA receptor antagonists are currently used in the treat ment of Par kinson's disease. The next few years could witness a break through in the treatment of neurological conditions as drugs that inte rfere with glutamatergic transmission become available for clinical us e.