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Reducing conditions significantly attenuate the neuroprotective efficacy of competitive, but not other NMDA receptor antagonists in vitro

Reducing conditions significantly attenuate the neuroprotective efficacy of competitive, but not other NMDA receptor antagonists in vitro
Reducing conditions significantly attenuate the neuroprotective efficacy of competitive, but not other NMDA receptor antagonists in vitro
Inappropriate activation of NMDA receptors during a period of cerebral ischaemia is a crucial event in the pathway leading to neuronal degeneration. However, significant research has failed to deliver a clinically active NMDA receptor antagonist, and competitive NMDA antagonists are ineffective in many experimental models of ischaemia. The NMDA receptor itself has a number of modulatory sites which may affect receptor function under ischaemic conditions. Using rat organotypic hippocampal slice cultures we have investigated whether the redox modulatory site affects the neuroprotective efficacy of NMDA receptor antagonists against excitotoxicity and experimental ischaemia (OGD). NMDA toxicity was significantly enhanced in cultures pretreated with a reducing agent. The noncompetitive antagonist MK-801 and a glycine-site blocker were equally neuroprotective in both normal and reduced conditions, but there was a significant rightward shift in the dose–response curves of the competitive antagonists APV and CPP and the uncompetitive antagonist memantine. OGD produced neuronal damage predominantly in the CA1 region, which was prevented by MK-801 and memantine, but not by APV or CPP. Inclusion of an oxidizing agent during the period of OGD had no effect alone, but significantly enhanced the neuroprotective potency of the competitive antagonists. These data clearly demonstrate that chemical reduction of the redox modulatory site of the NMDA receptor decreases the ability of competitive antagonists to block NMDA receptor-mediated neuronal damage, and that the reducing conditions which occur during simulated ischaemia are sufficient to produce a similar effect. This may have important implications for the design of future neuroprotective agents.
hippocampus, ischaemia, NMDA, organotypic slice culture, rat
0953-816X
3833-3842
Pringle, Ashley K.
6339ed95-c491-43a8-b2fb-2384466dc80d
Self, James
0f6efc58-ae24-4667-b8d6-6fafa849e389
Eshak, Marie
b310bf05-3fdb-44a5-b0b9-ade5f2c25654
Iannotti, Fausto
b7772bb7-d09c-4aca-8c5c-96e8da023c00
Pringle, Ashley K.
6339ed95-c491-43a8-b2fb-2384466dc80d
Self, James
0f6efc58-ae24-4667-b8d6-6fafa849e389
Eshak, Marie
b310bf05-3fdb-44a5-b0b9-ade5f2c25654
Iannotti, Fausto
b7772bb7-d09c-4aca-8c5c-96e8da023c00

Pringle, Ashley K., Self, James, Eshak, Marie and Iannotti, Fausto (2000) Reducing conditions significantly attenuate the neuroprotective efficacy of competitive, but not other NMDA receptor antagonists in vitro. European Journal of Neuroscience, 12 (11), 3833-3842. (doi:10.1046/j.1460-9568.2000.00272.x). (PMID:11069578)

Record type: Article

Abstract

Inappropriate activation of NMDA receptors during a period of cerebral ischaemia is a crucial event in the pathway leading to neuronal degeneration. However, significant research has failed to deliver a clinically active NMDA receptor antagonist, and competitive NMDA antagonists are ineffective in many experimental models of ischaemia. The NMDA receptor itself has a number of modulatory sites which may affect receptor function under ischaemic conditions. Using rat organotypic hippocampal slice cultures we have investigated whether the redox modulatory site affects the neuroprotective efficacy of NMDA receptor antagonists against excitotoxicity and experimental ischaemia (OGD). NMDA toxicity was significantly enhanced in cultures pretreated with a reducing agent. The noncompetitive antagonist MK-801 and a glycine-site blocker were equally neuroprotective in both normal and reduced conditions, but there was a significant rightward shift in the dose–response curves of the competitive antagonists APV and CPP and the uncompetitive antagonist memantine. OGD produced neuronal damage predominantly in the CA1 region, which was prevented by MK-801 and memantine, but not by APV or CPP. Inclusion of an oxidizing agent during the period of OGD had no effect alone, but significantly enhanced the neuroprotective potency of the competitive antagonists. These data clearly demonstrate that chemical reduction of the redox modulatory site of the NMDA receptor decreases the ability of competitive antagonists to block NMDA receptor-mediated neuronal damage, and that the reducing conditions which occur during simulated ischaemia are sufficient to produce a similar effect. This may have important implications for the design of future neuroprotective agents.

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More information

Published date: November 2000
Keywords: hippocampus, ischaemia, NMDA, organotypic slice culture, rat
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 357158
URI: http://eprints.soton.ac.uk/id/eprint/357158
ISSN: 0953-816X
PURE UUID: c3985494-92b1-43c4-87db-7cda2d3414e3
ORCID for Ashley K. Pringle: ORCID iD orcid.org/0000-0003-2421-4380
ORCID for James Self: ORCID iD orcid.org/0000-0002-1030-9963

Catalogue record

Date deposited: 20 Sep 2013 12:29
Last modified: 18 Feb 2021 17:06

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Contributors

Author: James Self ORCID iD
Author: Marie Eshak
Author: Fausto Iannotti

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