Effects of N(2-propylpentanoyl)urea on hippocampal amino acid neurotransmitters in spontaneous recurrent seizure rats

Background: N(2-propylpentanoyl) urea (VPU) is a new valproic acid (VPA) analog with higher anticonvulsant activity than its parent compound in various animal models including seizure acutely induced by pilocarpine. Objective: Investigate its effects on hippocampal amino acid neurotransmitters in spontaneous recurrent seizure (SRS) rats. Methods: Pilocarpine hydrochloride was used to induce status epilepticus (SE). Animals were visually observed for two hours/day for an episode of SRS for six weeks. Microdialysis experiment was performed to detect hippocampal amino acid neurotransmitters on those rats that developed SRS. Results: In comparison to normal rats, hippocampal glutamate, gamma-aminobutyric acid (GABA), and glycine, significantly increased in SRS rats. Occurrence of SRS in the faces of increased level of inhibitory neurotransmitters suggests the key role played by glutamate in the genesis and control of SRS. Based on the observation in pilocarpine-induced SE, the level of glutamate in SRS rats significantly decreased by a clinically effective anticonvulsant, VPA (300 and 600 mg/kg, i.p). Similar profile on hippocampal glutamate was also exhibited by VPU (50 and 100 mg/kg, i.p.). Conclusion: The possible role of VPU in controlling seizure in SRS rats and subsequently human temporal lobe epilepsy as VPA was suggested.

A Spontaneous Recurrent Seizure Bioassay for Anti-Epileptogenic Molecules

Drug design in epilepsy is now tackling a new target - epileptogenesis. This is the process whereby a normal brain becomes susceptible to recurrent seizures. One of the stumbling blocks in the design and discovery of new chemical entities as antiepileptogenics is the implementation of an appropriate biological model. Current models, such as the maximal electroshock model, are models of seizures, not models of epileptogenesis. To develop such a model, we have extended and modified a chronic pilocarpine spontaneous recurrent seizure (SRS) model for the purposes of developing a bioassay with which to screen new compounds for putative antiepileptogenic bioactivity.