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L-arginyl-3,4-spermidine is neuroprotective in several in vitro models of neurodegeneration and in vivo ischaemia without suppressing synaptic transmission

L-arginyl-3,4-spermidine is neuroprotective in several in vitro models of neurodegeneration and in vivo ischaemia without suppressing synaptic transmission
L-arginyl-3,4-spermidine is neuroprotective in several in vitro models of neurodegeneration and in vivo ischaemia without suppressing synaptic transmission
1. Stroke is the third most common cause of death in the world, and there is a clear need to develop new therapeutics for the stroke victim. To address this need, we generated a combinatorial library of polyamine compounds based on sFTX-3.3 toxin from which L-Arginyl-3,4-Spermidine (L-Arg-3,4) emerged as a lead neuroprotective compound. In the present study, we have extended earlier results to examine the compound's neuroprotective actions in greater detail.
2. In an in vitro ischaemia model, L-Arg-3,4 significantly reduced CA1 cell death when administered prior to induction of 60 min of ischaemia as well as when administered immediately after ischaemia. Surprisingly, L-Arg-3,4 continued to prevent cell death significantly when administration was delayed for as long as 60 min after ischaemia.
3. L-Arg-3,4 significantly reduced cell death in excitotoxicity models mediated by glutamate, NMDA, AMPA, or kainate. Unlike glutamate receptor antagonists, 300 muML-Arg-3,4 did not suppress synaptic transmission as measured by evoked responses in acute hippocampal slices.
4. L-Arg-3,4 provided significant protection, in vitro, in a superoxide mediated injury model and prevented an increase of superoxide production after AMPA or NMDA stimulation. It also decreased nitric oxide production after in vitro ischaemia and NMDA stimulation, but did so without inhibiting nitric oxide synthase directly.
5. Furthermore, L-Arg-3,4 was significantly neuroprotective in an in vivo model of global forebrain ischaemia, without any apparent neurological side-effects.
6. Taken together, these results demonstrate that L-Arg-3,4 is protective in several models of neurodegeneration and may have potential as a new therapeutic compound for the treatment of stroke, trauma, and other neurodegenerative diseases.
excitotoxicity, free-radical, hippocampus, ischaemia, nitric oxide, organotypic, polyamine, superoxide, tissue culture
0007-1188
1255-1268
Morrison lll, Barclay
8edd445f-9a42-45c4-ac05-e1aba0ff4ea1
Pringle, Ashley K.
6339ed95-c491-43a8-b2fb-2384466dc80d
McManus, Terence
550b4d89-472c-4c0e-b147-f27caeb438c8
Ellard, John
a43d123e-2927-4e0e-8c12-b93fba625811
Bradley, Mark
562b9add-34c4-4620-bfa1-c7c83a0f0900
Signorelli, Francesco
c26a6a22-d431-4e67-b107-45a0f8578078
Iannotti, Fausto
b7772bb7-d09c-4aca-8c5c-96e8da023c00
Sundstrom, Lars E.
bb62018d-0157-4274-a865-448ed12934bd
Morrison lll, Barclay
8edd445f-9a42-45c4-ac05-e1aba0ff4ea1
Pringle, Ashley K.
6339ed95-c491-43a8-b2fb-2384466dc80d
McManus, Terence
550b4d89-472c-4c0e-b147-f27caeb438c8
Ellard, John
a43d123e-2927-4e0e-8c12-b93fba625811
Bradley, Mark
562b9add-34c4-4620-bfa1-c7c83a0f0900
Signorelli, Francesco
c26a6a22-d431-4e67-b107-45a0f8578078
Iannotti, Fausto
b7772bb7-d09c-4aca-8c5c-96e8da023c00
Sundstrom, Lars E.
bb62018d-0157-4274-a865-448ed12934bd

Morrison lll, Barclay, Pringle, Ashley K., McManus, Terence, Ellard, John, Bradley, Mark, Signorelli, Francesco, Iannotti, Fausto and Sundstrom, Lars E. (2002) L-arginyl-3,4-spermidine is neuroprotective in several in vitro models of neurodegeneration and in vivo ischaemia without suppressing synaptic transmission. British Journal of Pharmacology, 137 (8), 1255-1268. (doi:10.1038/sj.bjp.0704986).

Record type: Article

Abstract

1. Stroke is the third most common cause of death in the world, and there is a clear need to develop new therapeutics for the stroke victim. To address this need, we generated a combinatorial library of polyamine compounds based on sFTX-3.3 toxin from which L-Arginyl-3,4-Spermidine (L-Arg-3,4) emerged as a lead neuroprotective compound. In the present study, we have extended earlier results to examine the compound's neuroprotective actions in greater detail.
2. In an in vitro ischaemia model, L-Arg-3,4 significantly reduced CA1 cell death when administered prior to induction of 60 min of ischaemia as well as when administered immediately after ischaemia. Surprisingly, L-Arg-3,4 continued to prevent cell death significantly when administration was delayed for as long as 60 min after ischaemia.
3. L-Arg-3,4 significantly reduced cell death in excitotoxicity models mediated by glutamate, NMDA, AMPA, or kainate. Unlike glutamate receptor antagonists, 300 muML-Arg-3,4 did not suppress synaptic transmission as measured by evoked responses in acute hippocampal slices.
4. L-Arg-3,4 provided significant protection, in vitro, in a superoxide mediated injury model and prevented an increase of superoxide production after AMPA or NMDA stimulation. It also decreased nitric oxide production after in vitro ischaemia and NMDA stimulation, but did so without inhibiting nitric oxide synthase directly.
5. Furthermore, L-Arg-3,4 was significantly neuroprotective in an in vivo model of global forebrain ischaemia, without any apparent neurological side-effects.
6. Taken together, these results demonstrate that L-Arg-3,4 is protective in several models of neurodegeneration and may have potential as a new therapeutic compound for the treatment of stroke, trauma, and other neurodegenerative diseases.

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More information

Published date: 2002
Keywords: excitotoxicity, free-radical, hippocampus, ischaemia, nitric oxide, organotypic, polyamine, superoxide, tissue culture

Identifiers

Local EPrints ID: 27666
URI: http://eprints.soton.ac.uk/id/eprint/27666
ISSN: 0007-1188
PURE UUID: a43cb25e-e7b9-4238-ba43-e6eda2656ef1
ORCID for Ashley K. Pringle: ORCID iD orcid.org/0000-0003-2421-4380

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Date deposited: 25 Apr 2006
Last modified: 16 Mar 2024 02:48

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Contributors

Author: Barclay Morrison lll
Author: Terence McManus
Author: John Ellard
Author: Mark Bradley
Author: Francesco Signorelli
Author: Fausto Iannotti
Author: Lars E. Sundstrom

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