Effect of n-(2-propylpentanoyl)urea on pilocarpine-induced seizure in rats

Abstract

The present study was aimed to investigate the effects and underlying mechanisms of N-(2-propylpentanoyl) urea (VPU) in pilocarpine-induced seizure in rats. We studied an anticonvulsant activity of VPU against pilocarpind-induced seizure and also the effects of VPU on neurochemical changes (excitatory and inhibitory amino acid neurotransmitters in the hippocampus), morphological changes in hippocampus (CA1 and CA3 regions), hippocampal lipid peroxidation levels and brain mitochondrial function. VPU was found to be more effective than VPA while the median effective dose (ED50) of VPU was 49 mg/kg B.W., the corresponding value for VPA was 322 mg/kg B.W. In microdialysis studies, VPU (50 and 100 mg/kg B.W.) and VPA (300 and 600 mg/kg B.W.) demonstrated the same spectrum to significantly reduce both hippocampal excitatory and inhivbitory amino acid neutransmitters especially the greatest depression on glutamate in pilocarpine-induced seizure rats. It is likely that the anticonvulsant activity of VPU and VPA in pilocarpine-induced seizure rats is due, at least inpart, to reduction of an abnormally high extracellular level of excitatory amino acid neurotransmitters. In addition to anticonsulvant activity, pretreatment of either VPU or VPA significantly hippocampal neuronal damage and the enhancement of malonaldehyde (MDA) induced by pilocarpine. In brain mitochondrial function, VPU behaved as an uncoupler by stimulating state 4 respiration whereas it was successfully restored pilocarpine-induced inhibition of state 3 respiration when glutamate plus malate were used as the substrates, leading to slightly increase ATP synthesis. In contrast VPA produced no deterctable effect on state 3, state 4 respiration and ATP synthesis. VPU reduced the enhancement of lipid peroxidation and restoring mitochondria dysfunction evoked by pilocarpine. This might propse the efficacy of VPU in the attenuation of the neuronal damage induced by pilocaroine.However VPA might exerted different mechanism of neuroprotection from VPU. The results obtained suggest that the protection of VPU against pilocarpine-induced status epilepticus might be accounted by its ability to reduce the levels of excitatory amino acid which were significantly increased by pilocarpine. The reduction the enhancement of lipid peroxidation and restoring mitochondria dysfunction might be explain the neuroprotective activity of VPU in pilocarpine-induced seizure rats. We also suggest that some other mechanisms than those being demonstrated in the present study should also be further investigated.