Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 368, Issue 3, pp 216–224 | Cite as

Characterisation of a novel class of polyamine-based neuroprotective compounds

  • Ashley K. Pringle
  • Barclay MorrisonIII
  • Mark Bradley
  • Fausto Iannotti
  • Lars E. Sundstrom
Original 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.

Keywords

Organotypic culture Hippocampus Hypoxia Polyamine Neuroprotection 

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Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Ashley K. Pringle
    • 1
  • Barclay MorrisonIII
    • 1
  • Mark Bradley
    • 2
  • Fausto Iannotti
    • 1
  • Lars E. Sundstrom
    • 1
  1. 1.Clinical NeurosciencesUniversity of SouthamptonSouthamptonUK
  2. 2.Combinatorial Centre of ExcellenceUniversity of SouthamptonSouthamptonUK

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