Hydroxycinnamic acid amide derivatives of polyamines reverse spermine-induced CNS excitation

Abstract

The aim of this study was to examine the acute effect of a range of novel hydroxycinnamic acid derivatives of spermine on the development of spermine-induced CNS excitation and convulsions in female Laca mice, and to assess the chronic adverse behavioural effect profile of these compounds over a 5day period. Four of the six novel polyamine analogues dose-dependently inhibited body tremor and tonic convulsions caused by spermine, when administered centrally (icv) or peripherally (ip). BU43b was the most potent analogue tested, but BU31b, 33b, and 36b were also effective (p<0.01, Mann–Whitney U test). A similar profile of effectiveness was seen with peripheral and central administration, indicating that the analogues may cross the blood brain barrier. More chronic investigation of the adverse effects of the compounds administered alone over 5days of observation indicated that the drugs were well tolerated, only causing reduced locomotor activity on the first day of the study and mild changes in behaviours linked to CNS and ANS function. It is likely that NMDA receptor NR2B subunit inhibition is involved in the anticonvulsant effect of these novel analogues, but other mechanisms may also be involved. These novel polyamine derivatives warrant further investigation of their therapeutic potential in treating epilepsy and CNS disorders where excitotoxicity is implicated.