Abstracts

RATIONALE: This study compared the anti-epileptogenic activity of the antiepileptic drug (AED) levetiracetam (LEV) and of the reference AED valproate (VPA) in a rat model of pilocarpine-induced epileptogenesis. Spontaneous seizures, hippocampal field potentials and neuropathological changes in the brain induced by status epilepticus (SE) following pilocarpine administration were recorded after three weeks continuous infusion (via Alzet pumps) of either vehicle, LEV or VPA.
METHODS: The SE induced in male Sprague-Dawley rats by 375 mg/kg ip. Pilocarpine (PILO) was terminated with diazepam 10 mg/kg iv, 30 min after secondary generalization (Vanneste-Goemaere [italic]et al[/italic]., [italic]Epilepsia[/italic] 40, Suppl. 7, 38, 1999). Subsequently, separate groups of rats received either LEV 54 mg/kg ip, followed by 21 days infusion of LEV (50, or 150, or 300 mg/kg/d), or VPA 200 mg/kg ip, followed by 21 days infusion of VPA (600 mg/kg/d), or saline. Three days after terminating the chronic infusion: [italic]i.[/italic] the incidence of spontaneous seizures was evaluated during 72 h continuous video-EEG recording, [italic]ii.[/italic] evoked field potentials were recorded in DG and CA1 hippocampal areas of urethane-anesthetized rats, and [italic]iii.[/italic] histopathological changes were evaluated in the hippocampus, olfactory cortex, thalamus, amygdala and ventricles, on 5 [mu]m-thick coronal paraffin-embedded brain sections, stained with cresyl violet.
RESULTS: [italic]i.[/italic] Partial and generalized spontaneous seizures, were recorded in 25 [ndash] 70 % of the rats in both the vehicle-, LEV- and VPA-infused groups. [italic]ii.[/italic] The amplitude of the population spikes evoked in the DG area was dose-dependently lower in LEV- vs. vehicle-infused rats, while the infusion of VPA produced only a modest decrease in amplitude. The low (20 ms) inter-stimulus interval paired-pulse inhibition in hippocampal CA1 area was completely abolished in PILO-treated, vehicle-infused rats, but was significantly restored by the infusion of LEV. In contrast, the infusion of VPA only caused a non-significant tendency to restore paired-pulse inhibition. [italic]iii.[/italic] LEV, 150 or 300 mg/kg/d, tended to reduce the PILO-induced hippocampal necroses, while no difference with respect to control group was observed in the rats infused with VPA.
CONCLUSIONS: Three weeks infusion of LEV, 150 or 300 mg/kg/d, opposed the epileptogenic effect on the hippocampal field potentials recorded in anesthetized rats and tended to decrease some neuropathological consequences of PILO-induced generalized seizures. In contrast, VPA (600 mg/kg/d) had less of an effect than LEV on hippocampal field potentials and did not affect the neuropathological changes.
Support: UCB SA
Disclosure: Salary - Klitgaard - UCB SA
Matagne - UCB SA
Vanneste-Goemaere - UCB SA
Margineanu - UCB SA