Preliminary studies of anticonvulsion mechanisms of N-(2-propylpentanoyl) urea

Abstract

The present studies was aimed to investigate the anticonvulsant activity with regards to duration of action as well as neurotoxicity of a newly synthesized valproic analogue, N-(2-propylpentanoyl) urea (VPU), which has been previously reported to be a potent and broad spectrum anticonvulsant in animal models. Maximal electroshock (MES) and rotorod test were used to assess the anticonvulsant and neurotoxicity of VPU in mice respectively. In addition, in vitro degradation using rat brain and liver homogenate and in vivo microdialysis experiment on conscious freely moving rats were performed to search for possible mode of action of VPU. Superiority of VPU to VPA in terms of higher potency in protection against MES and lower neurological toxicity as assessed by rotorod test was evident throughout the observation of 12 hours after dosing. VPU was also orally active demonstrating the ED50 approximately 6 times higher than its corresponding value by intraperitoneal route. VPU was not degraded to VPA either by brain or liver homogenate. Therefore, it is likely that VPU per se and/or any of its metabolites other than VPA accounts for the anticonvulsant observed. Based on the results that the alteration of ED50 of VPU and VPA exhibited within the observation period of 12 hours were similar, it is speculative that VPU may resemble VPA in pharmacokinetic characters. Microdialysis studies on awake rats revealed different profile of responses on cortical amino acid neurotransmitters exhibited by VPU and VPA. VPU was found to exert no significant effect on the level of cortical aspartate, glycine and GABA while a non dose-dependent reduction was observed on glutamate level. Therefore unlike VPA which appeared to exert at least part of its effect by an increment of cortical GABA and glycine, other mechanisms may underly anticonvulsant activity of VPU and they remain to be further elucidated. Thus, it may conclude herein that despite being an analogue of VPA, VPU differ from its parent compound with regards to potency, toxicity and mechanism of action. Extensive studies are needed to clarify pharmacokinetic, pharmacodynamic, toxicity and precise mechanism of action of this compound.