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), 216-224. (doi:10.1007/s00210-003-0778-4).
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Description/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.
| Item Type: | Article |
|---|---|
| ISSNs: | 0028-1298 (print) |
| Related URLs: | |
| Keywords: | organotypic culture, hippocampus, hypoxia, polyamine, neuroprotection |
| Subjects: | R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry |
| Divisions: | University Structure - Pre August 2011 > School of Medicine > Clinical Neurosciences |
| Item ID: | 27690 |
| Date Deposited: | 28 Apr 2006 |
| Last Modified: | 01 Apr 2012 03:00 |
| Contributors: | Pringle, Ashley K. (Author) Morrison III, Barclay (Author) Bradley, Mark (Author) Iannotti, Fausto (Author) Sundstrom, Lars E. (Author) |
| Date: | 2003 |
| Status: | Published |
| Contact Email Address: | akp1@soton.ac.uk |
| URI: | http://eprints.soton.ac.uk/id/eprint/27690 |
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