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

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.

The pre-ischaemic neuroprotective effects of the polyamine analogues BU43b and BU36b in permanent and transient focal cerebral ischaemia models in mice.

The present study investigated the neuroprotective potential of two novel polyamine analogues, BU43b and BU36b, when administered 30 min prior to cerebral ischaemia. Neuroprotection in a permanent and a transient focal cerebral ischaemia mouse model (induced by intraluminal middle cerebral artery occlusion (MCAO)) was investigated using a range of histological and behavioural assessments. In the permanent ischaemia model, BU43b reduced oedema and showed a trend towards reduction in %HLV (percentage hemisphere lesion volume) when administered at a dose of 30 mg/kg i.p. Following transient ischaemia, treatment with BU43b decreased the %HLV and reduced oedema when administered at 30 mg/kg. BU43b also improved the locomotor activity (LMA) in MCAO mice at both 20 mg/kg and 30 mg/kg doses. BU36b was less effective than BU43b in both the permanent and the transient models, with its most pronounced effect being a trend towards reduction in oedema in both models. These results demonstrate that BU43b administered 30 min before ischaemia provided a good level of neuroprotection in the two models of cerebral ischaemia used and may have potential as a neuroprotective treatment for stroke.

Preparation and biological assessment of hydroxycinnamic acid amides of polyamines.

Many plants contain hydroxycinnamic acid conjugates of polyamines that are remarkably similar in general structure to the acylated polyamines found in spider and wasp toxins. In an effort to determine whether these compounds might play a role in the chemical defense of plants against arthropod pests we synthesized a variety of analogues of the coumaric (4-hydroxycinnamic) acid conjugates of di-, tri-, and tetraamines using common protection and acylation strategies. N(1)- and N(8)-coumaroyl spermidine were tested in feeding trials with insect larvae including the European corn borer (Ostrinia nubilalis), the tobacco budworm (Heliothis verescens) and the oblique banded leaf roller (Choristoneura rosaceana). Antifeedant assays with the rice weevil Sitophilus oryzae were also performed. Neither the naturally occurring coumaric acid conjugates of polyamines nor their analogues showed notable toxicity towards insects, despite precautions to maintain these easily oxidized materials in the wet diet. However, more direct bioassays of these compounds on glutamate dependent neuroreceptors including the deep abdominal extensor muscles of crayfish, or mammalian NMDA, delta2, and AMPA receptors, clearly showed that these compounds were inhibitory. N(1)-Coumaoryl spermine, a dodecyl and a cyclohexyl analogue were especially active at NMDA NR1/NR2B receptors. The latter had an IC(50) of 300 microM in the crayfish. N(1)-Coumaroyl spermine had an IC(50) in the crayfish preparation of 70-300 microM and against the mammalian NR1/NR2B receptor of 38 nM. Structure-activity variations show similar trends of length and hydrophobicity as has been seen previously with analogues of spider toxins. We conclude from this work that while the coumaric acid polyamine conjugates are active when directly applied to neuroreceptors, they show no overt toxicity when ingested by insect larvae.