ROLE OF EXCITATORY AMINO-ACIDS IN NEUROPA THOLOGY

Citation
Si. Wikinski et Gb. Acosta, ROLE OF EXCITATORY AMINO-ACIDS IN NEUROPA THOLOGY, Medicina, 55(4), 1995, pp. 355-365
Citations number
32
Categorie Soggetti
Medicine, General & Internal
Journal title
ISSN journal
00257680
Volume
55
Issue
4
Year of publication
1995
Pages
355 - 365
Database
ISI
SICI code
0025-7680(1995)55:4<355:ROEAIN>2.0.ZU;2-1
Abstract
Excitatory amino acids (EAA) became known as neurotransmitters of the central nervous system (CNS) in the last decade. The most studied EAA are glutamate and aspartate. Both are synthetized by the same mechanis m as gama-aminobutyric acid. (Fig. 1). Glutamate is widely distributed in the CNS and the spinal cord, being the areas of higher concentrati on the cerebral cortex, the hypocampus and the cerebellum. There have been identified two type of receptors for glutamate: ionotropic and me tabotropic. The former includes three different types: NMDA, AMPA and KA. NMDA receptor is coupled to a Na+ and Ca2+ channel being the secon d ion the most important one. This receptor has several sites of bindi ng for various substances. Along with the site for N-methyl-D-aspartat e, which binds glutamate and/or aspartate, there have been identified a site for the binding of glycine (which is different from the strychn ine sensitive one), a site for pollamines such as spermine and spermid ine, and a site for the binding of Zn2+ (Table 1). AMPA receptor is as sociated to a Ca2+-Na+ channel, being in this case the Na+ the most im portant ion. There are two metabotropic type receptors: L-AP4 and tran s-ACPD. Both are coupled to a G protein and agonists exert their actio n increasing phospholipase C activity which in turn induces an increme nt of IP3 and diacyl-glicerol, and a consecutive releasing of Ca2+ fro m intracellular stores. EAA play a role in some physiological processe s. One of them is long-term potentiation (LTP), an electrochemical phe nomenon involved in memory consolidation. Antagonists of NMDA and AMPA receptor prevent the development of LTP, and conversely, the agonist of glycine site of NMDA receptor -D-cycloserine- facilitates memory co nsolidation. Since 1957, EAA are considered neurotoxic substances and there are many indirect evidences to support this statement. Pathogene sis of neuronal damage elicited by EAA involves the events shown in Fi g. 3. Prevention of the cascade of events that provokes neurotoxicity may be achieved by NMDA antagonists, but once it has begun it may be o nly aborted substracting the Ca2+ from the medium, using nifedipine or blocking AMPA receptor with an antagonist (CNQX). EAA have been shown to play a toxic role in neuronal damage induced by ischemia. Research using various experimental models demonstrated that NMDA receptor ant agonists (i.e. MK 801) blocks postischemic damage. Interventions at va rious levels of the pathogenic cascade shown in Fig. 4 provoke the sam e results. There is enough evidence to suspect that NMDA and AMPA rece ptors are altered in epilepsy. NMDA antagonists (i.e. MK801 or AP5) pr event the development of epileptic seizures induced by kindling; CNQX, an AMPA antagonist, blocks the increase in electrical activity induce d by K+ in slices of hypocampus; felbamate, an antiepileptic drug, blo cks the glycine site (not strychnine sensitive) decreasing NMDA recept or activity. Several neurodegenerative disorders have been associated with exogenous administration or accidental intake of EAA. (i.e. neuro latirism, Guam disease). Similarities between these diseases and later al amiotrophic sclerosis indicate that in the latter EAA may play a pa thogenic role. Finally, the psychotomimetic effect of phencyclidine (a n antagonist of NMDA receptor) suggests that in schizophrenia, togethe r with dopaminergic neurotransmission impairment, some dysfunction of glutamate pathways may be present.