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Reducing conditions produce a loss of neuroprotective efficacy of competitive but not non-competitive antagonists in a model of NMDA-mediated excitotoxicity in organotypic hippocampal slice cultures

Reducing conditions produce a loss of neuroprotective efficacy of competitive but not non-competitive antagonists in a model of NMDA-mediated excitotoxicity in organotypic hippocampal slice cultures
Reducing conditions produce a loss of neuroprotective efficacy of competitive but not non-competitive antagonists in a model of NMDA-mediated excitotoxicity in organotypic hippocampal slice cultures
Experimental data indicate that NMDA receptor activation is strongly implicated in the pathogenesis of cerebral ischaemia. However, the results from in vivo studies are equivocal, with NMDA antagonists being active in only some models. It has recently been demonstrated that competitive and non-competitive NMDA antagonists behave differently under normal and ischaemic conditions. These studies have used organotypic hippocampal slice cultures to investigate whether this disparity is due to redox-modulation of the NMDA receptor which occurs in ischaemia. NMDA-mediated toxicity was concentration dependent with little damage occurring with less than 10 µM NMDA and maximal damage produced by 30 µM. NMDA toxicity was significantly enhanced by pre-treatment with 1 mM dithiothreitol, a reducing agent, such that damage occurred at 1 nM NMDA, and maximal damage was produced by 10 µM. The efficacy of MK-801 was not altered by reducing conditions, but the EC50 of the competitive antagonist APV was increased by 20-fold. These data strongly suggest that the neuroprotective efficacy of NMDA antagonists is significantly altered under ischaemic conditions, and that more beneficial effects will be obtained with antagonists having a higher affinity for the receptor in the reduced configuration.
978-3-7091-7257-5
0065-1419
79-80
Springer
Pringle, A.K.
6339ed95-c491-43a8-b2fb-2384466dc80d
Self, J.
0f6efc58-ae24-4667-b8d6-6fafa849e389
Iannotti, Fausto
b7772bb7-d09c-4aca-8c5c-96e8da023c00
Pringle, A.K.
6339ed95-c491-43a8-b2fb-2384466dc80d
Self, J.
0f6efc58-ae24-4667-b8d6-6fafa849e389
Iannotti, Fausto
b7772bb7-d09c-4aca-8c5c-96e8da023c00

Pringle, A.K., Self, J. and Iannotti, Fausto (2000) Reducing conditions produce a loss of neuroprotective efficacy of competitive but not non-competitive antagonists in a model of NMDA-mediated excitotoxicity in organotypic hippocampal slice cultures. In, Brain Edema XI. (Acta Neurochirurgica Supplements, , (doi:10.1007/978-3-7091-6346-7_16), 76) Springer, pp. 79-80. (doi:10.1007/978-3-7091-6346-7_16).

Record type: Book Section

Abstract

Experimental data indicate that NMDA receptor activation is strongly implicated in the pathogenesis of cerebral ischaemia. However, the results from in vivo studies are equivocal, with NMDA antagonists being active in only some models. It has recently been demonstrated that competitive and non-competitive NMDA antagonists behave differently under normal and ischaemic conditions. These studies have used organotypic hippocampal slice cultures to investigate whether this disparity is due to redox-modulation of the NMDA receptor which occurs in ischaemia. NMDA-mediated toxicity was concentration dependent with little damage occurring with less than 10 µM NMDA and maximal damage produced by 30 µM. NMDA toxicity was significantly enhanced by pre-treatment with 1 mM dithiothreitol, a reducing agent, such that damage occurred at 1 nM NMDA, and maximal damage was produced by 10 µM. The efficacy of MK-801 was not altered by reducing conditions, but the EC50 of the competitive antagonist APV was increased by 20-fold. These data strongly suggest that the neuroprotective efficacy of NMDA antagonists is significantly altered under ischaemic conditions, and that more beneficial effects will be obtained with antagonists having a higher affinity for the receptor in the reduced configuration.

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Published date: 2000
Organisations: Faculty of Medicine

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Local EPrints ID: 357163
URI: http://eprints.soton.ac.uk/id/eprint/357163
ISBN: 978-3-7091-7257-5
ISSN: 0065-1419
PURE UUID: bee93c62-4e2f-4240-865f-dda0d06aa8b2
ORCID for A.K. Pringle: ORCID iD orcid.org/0000-0003-2421-4380
ORCID for J. Self: ORCID iD orcid.org/0000-0002-1030-9963

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Date deposited: 20 Sep 2013 13:33
Last modified: 18 Feb 2021 17:06

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Author: A.K. Pringle ORCID iD
Author: J. Self ORCID iD
Author: Fausto Iannotti

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