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Characterisation of a novel class of polyamine-based neuroprotective compounds

Pringle, Ashley K., Morrison III, Barclay, Bradley, Mark, Iannotti, Fausto and Sundstrom, Lars E. (2003) Characterisation of a novel class of polyamine-based neuroprotective compounds Naunyn-Schmiedeberg's Archives of Pharmacology, 368, (3), pp. 216-224. (doi:10.1007/s00210-003-0778-4).

Record type: Article

Abstract

Prolonged cerebral ischaemia initiates complex intra- and inter-cellular signalling cascades ultimately resulting in neuronal death. Well-characterised mediators of ischaemic cell death are glutamate, free radicals and nitric oxide. Many drugs that block these mechanisms are neuroprotective in vitro, but have unfavourable side-effect profiles in man. We have recently demonstrated that the compound L-arginyl-3,4-spermidine (L-Arg3,4) is neuroprotective in vitro through an interaction with several of these mechanisms, and prevents ischaemic neurodegeneration in vivo with no gross side effects. In this study, we have used solid-phase combinatorial chemistry, to synthesise a number of analogues of L-Arg3,4, and investigate the structure-activity relationship using an in vitro, organotypic hippocampal slice culture model of cerebral ischaemia. A number of molecular features were identified which were essential for the neuroprotective activity including the requirement for a positive charge and an amino acid in the L-configuration. Relatively minor alterations to both the terminal arginine and polyamine moieties significantly attenuated neuroprotective efficacy. Our data implies that these compounds are neuroprotective through a currently undefined mechanism rather than non-specific ionic interactions described previously for other polyamine-containing compounds.

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More information

Published date: 2003
Keywords: organotypic culture, hippocampus, hypoxia, polyamine, neuroprotection

Identifiers

Local EPrints ID: 27690
URI: http://eprints.soton.ac.uk/id/eprint/27690
ISSN: 0028-1298
PURE UUID: 5e3d1daa-d712-48f0-b8b7-ff914c49eaaa
ORCID for Ashley K. Pringle: ORCID iD orcid.org/0000-0003-2421-4380

Catalogue record

Date deposited: 28 Apr 2006
Last modified: 17 Jul 2017 16:04

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Contributors

Author: Barclay Morrison III
Author: Mark Bradley
Author: Fausto Iannotti
Author: Lars E. Sundstrom

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