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Titolo:
The role of excitotoxicity in neurodegenerative disease: Implications for therapy
Autore:
Doble, A;
Indirizzi:
Rhone Poulenc Rorer SA, Dept Neurosci, F-92165 Antony, France Rhone Poulenc Rorer SA Antony France F-92165 sci, F-92165 Antony, France
Titolo Testata:
PHARMACOLOGY & THERAPEUTICS
fascicolo: 3, volume: 81, anno: 1999,
pagine: 163 - 221
SICI:
0163-7258(199903)81:3<163:TROEIN>2.0.ZU;2-M
Fonte:
ISI
Lingua:
ENG
Soggetto:
METHYL-D-ASPARTATE; AMYOTROPHIC-LATERAL-SCLEROSIS; EXCITATORY AMINO-ACIDS; CENTRAL-NERVOUS-SYSTEM; NMDA-RECEPTOR ANTAGONIST; MIDDLE CEREBRAL-ARTERY; METABOTROPIC GLUTAMATE RECEPTORS; MOTOR-NEURON DISEASE; GLYCINE MODULATORY SITE; AMPA-KAINATE RECEPTORS;
Keywords:
glutamic acid; excitotoxicity; calcium; stroke; amyotrophic lateral sclerosis; NMDA;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
693
Recensione:
Indirizzi per estratti:
Indirizzo: Doble, A Rhone Poulenc Rorer SA, Dept Neurosci, 20 Ave Raymond Aron,TRI 109, F-92165 Rhone Poulenc Rorer SA 20 Ave Raymond Aron,TRI 109 Antony France F-92165
Citazione:
A. Doble, "The role of excitotoxicity in neurodegenerative disease: Implications for therapy", PHARM THERA, 81(3), 1999, pp. 163-221

Abstract

Glutamic acid is the principal excitatory neurotransmitter in the mammalian central nervous system. Glutamic acid binds to a variety of excitatory amino acid receptors, which are ligand gated ion channels. It is activation of these receptors that leads to depolarisation and neuronal excitation, In normal synaptic functioning, activation of excitatory amino acid receptors is transitory. However, if, for any reason, receptor activation becomes excessive or prolonged, the target neurones become damaged and eventually die. This process of neuronal death is called excitotoxicity and appears to involve sustained elevations of intracellular calcium levels. Impairment of neuronal energy metabolism may sensitise neurones to excitotoxic cell death. The principle of excitotoxicity has been well established experimentally, both in in vitro systems and in vivo, following administration of excitatoryamino acids into the nervous system. A role for excitotoxicity in the aetiology or progression of several human neurodegenerative diseases has been proposed, which has stimulated much research recently. This has led to the hope that compounds that interfere with glutamatergic neurotransmission may be of clinical benefit in treating such diseases. However, except in the case of a few very rare conditions, direct evidence for a pathogenic role forexcitotoxicity in neurological disease is missing. Much attention has beendirected at obtaining evidence for a role for excitotoxicity in the neurological sequelae of stroke, and there now seems to be little doubt that sucha process is indeed a determining factor in the extent of the lesions observed. Several clinical trials have evaluated the potential of antiglutamatedrugs to improve outcome following acute ischaemic stroke, but to date, the results of these have been disappointing. In amyotrophic lateral sclerosis, neurolathyrism, and human immunodeficiency virus dementia complex, several lines of circumstantial evidence suggest that excitotoxicity may contribute to the pathogenic process. An antiglutamate drug, riluzole, recently has been shown to provide some therapeutic benefit in the treatment of amyotrophic lateral sclerosis. Parkinson's disease and Huntington's disease are examples of neurodegenerative diseases where mitochondrial dysfunction may sensitise specific populations of neurones to excitotoxicity from synaptic glutamic acid. The first clinical trials aimed at providing neuroprotection with antiglutamate drugs are currently in progress for these two diseases. (C) 1999 Elsevier Science Inc. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 06/04/20 alle ore 02:12:26