       Document 0143
 DOCN  M9620143
 TI    Excitatory amino acid receptors and neurodegeneration.
 DT    9602
 AU    Doble A; Departement Biologie, Rhone-Poulenc Rorer S.A.,;
       Vitry-sur-Seine, France.
 SO    Therapie. 1995 Jul-Aug;50(4):319-37. Unique Identifier : AIDSLINE
       MED/96027110
 AB    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.
 DE    Animal  AIDS Dementia Complex/METABOLISM  Central Nervous
       System/INJURIES/METABOLISM  Cerebrovascular Disorders/METABOLISM
       Glutamic Acid/METABOLISM  Human  *Nerve Degeneration  Receptors,
       Glutamate/CLASSIFICATION/*METABOLISM  JOURNAL ARTICLE  REVIEW  REVIEW,
       ACADEMIC

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

