An investigation into the behavioural effects of polyamines, polyamine antagonsits and novel compounds in vivo

Abstract

The polyamines, putrescine, spermidine and spermine are ubiquitous compounents of eukaryotric cells in nature and are found in high concentrations in brain tissue. Polyamines have been implicated in cell growth, differentiation and nerve regeneration, but at high doses are neurotoxic. Administration of spermine (100μg icv) causes CNS excitation culminating in fatal tonic convulsions, within 8 hours. It is thought that spermine mediates this effect at least in part, through enhancement of activity on the NMDA receptor through positive modulatory extracellular binding site on the NMDA macrocomplex. To further enhance understanding of the mechanism of action of polyamines the antagonist potential of NMDA receptor antagonist, calcium channel antagonists, N1- dansylspermine and 6 novel polyamine analogues (Bu 31b, Bu 37b, Bu 33b, Bu 40b, Bu 36b and Bu 43b) from Brock University Canada, was assessed in the spermine CNS excitation model. The investigation revealed that the NMDA antagonists ifenprodil, eliprodil, arcaine and memantine inhibited the spermine-induced CNS excitation. L-type calcium channel antagonists, nisoldipine and nitrendipine, also were shown to inhibit the development of spermine-induced convulsions. N1-dansylspermine, a potent polyamine antagonist, also inhibited the effect of spermine. Of the novel polyamine analogues, Bu 36b and Bu 43b reduced the development of CNS excitation to the greatest degree. Bu 3Ib and Bu 40b did not have a pronounced inhibitory effect on spermine-induced convulsions. However, Bu 33b and Bu 37b did elicit an inhibitory effect on the development of spermine- induced CNS excitation.