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Titre du document / Document title

Glutamate-stimulated peroxynitrite production in a brain-derived endothelial cell line is dependent on N-methyl-D-aspartate (NMDA) receptor activation

Auteur(s) / Author(s)

SCOTT G. S. (1) ; BOWMAN S. R. (1) ; SMITH T. (2) ; FLOWER R. J. (1) ; BOLTON C. (1) ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

(1) Centre of Biochemical Pharmacology & Experimental Pathology, The William Harvey Research Institute, St. Bartholomew's Hospital Medical College and the London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, ROYAUME-UNI
(2) NeuMatRx, Truro, Cornwall TR3 6NT, ROYAUME-UNI

Résumé / Abstract

There is accumulating and convincing evidence indicating a role for glutamate in the pathogenesis of the human demyelinating disease multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, demonstrate that pharmacological inhibition of specific glutamate receptors suppresses neurological symptoms and prevents blood-brain barrier (BBB) breakdown. The mechanisms through which glutamate influences BBB function during EAE remain unclear. Glutamate triggers the production of nitric oxide and superoxide, which can lead to the formation of peroxynitrite (ONOO-). Recent studies have implicated ONOO- in the loss of neurovascular integrity during EAE. We propose that glutamate contributes to BBB breakdown via the actions of ONOO-. The present investigation examined glutamate-induced ONOO formation in the b.End3 brain-derived endothelial cell line. b.End3 cells were incubated with a concentration range of glutamate and ONOO- production was assessed over time. Results showed a concentration-and time-dependent increase in ONOO- levels in glutamate-treated cells that were suppressed by selective and non-selective inhibitors of ONOO--mediated reactions. Specific activation of b.End3-associated NMDA receptors also resulted in a concentration-dependent increase in ONOO production. The ability of b.End3 cells to respond to the presence of glutamate was confirmed through the detection of NMDA receptor immnuoreactivity in cell extracts. In addition, the use of the NMDA receptor antagonists MK-801 and memantine reduced glutamate-mediated ONOO- generation from b.End3 cells. The data reinforce the important relationship between glutamate and the NMDA receptor, positioned at neurovascular sites, which maybe of particular relevance to the pathogenesis of demyelinating disease.

Revue / Journal Title

Biochemical pharmacology    ISSN  0006-2952   CODEN BCPCA6 

Source / Source

2007, vol. 73, no2, pp. 228-236 [9 page(s) (article)] (67 ref.)

Langue / Language

Anglais

Editeur / Publisher

Elsevier, Amsterdam, PAYS-BAS  (1958) (Revue)

Mots-clés anglais / English Keywords

Central nervous system

;

Neurotransmitter

;

Excitatory aminoacid

;

Nitric oxide

;

NMDA receptor

;

Glutamate receptor

;

NMDA

;

Cell line

;

Established cell line

;

In vitro

;

Endothelial cell

;

Encephalon

;

Glutamate

;

Mots-clés français / French Keywords

Système nerveux central

;

Neurotransmetteur

;

Aminoacide excitateur

;

Peroxynitrite

;

Azote monoxyde

;

Récepteur NMDA

;

Récepteur glutamate

;

NMDA

;

Lignée cellulaire

;

Lignée cellulaire établie

;

In vitro

;

Cellule endothéliale

;

Encéphale

;

Glutamate

;

Mots-clés espagnols / Spanish Keywords

Sistema nervioso central

;

Neurotransmisor

;

Aminoácido excitador

;

Nitrógeno monóxido

;

Receptor NMDA

;

Receptor glutámato

;

NMDA

;

Línea celular

;

Línea celular establecida

;

In vitro

;

Célula endotelial

;

Encéfalo

;

Glutamato

;

Mots-clés d'auteur / Author Keywords

Peroxynitrite

;

Nitric oxide

;

Glutamate

;

N-Methyl-D-aspartate receptor

;

Brain-derived endothelial cells

;

Localisation / Location

INIST-CNRS, Cote INIST : 1418, 35400015930580.0070

Nº notice refdoc (ud4) : 18430185



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