Abstracts

During conditions of increased glutamate release such as seizures, group I metabotropic glutamate receptors (mGluRs) activate many second messenger pathways that contribute to epileptogenesis. Exposure to the group I mGluR agonist (RS)-3,5-dihyroxyphenylglycine (DHPG) results in the induction of epileptiform discharges in hippocampal slices that persist for hours after DHPG is removed. We investigated effects of levetiracetam (LEV) and valproate (VPA), two anti-epileptic drugs that retard kindling epileptogenesis, in the group I mGluR [italic]in vitro[/italic] model of epileptogenesis. Hippocampal slices were prepared from Sprague-Dawley rats (100-200 g), and incubated either in the presence of DHPG (100 [mu]M) alone or with either LEV or VPA followed by DHPG for 90-120 min. Slices were transferred to an interface chamber and bathed in artificial cerebrospinal fluid (ACSF, [K⁺][sub]o[/sub] = 5 mM) for 1 hour and then monitored extracellularly in the CA3 region for spontaneously occurring epileptiform activity that consisted of either brief interictal ( [lt] 500 ms) or prolonged ([gt]2s) ictal-like discharges. Following evaluation slices were exposed to bicuculline (BMI, 10 [mu]M) and assessed for epileptiform activity. LEV (300 [mu]M) applied with DHPG resulted in only 12% of slices demonstrating ictal activity and 17% with interictal activity in ACSF (n = 41). Control slices prepared from the same animals and exposed to DHPG alone demonstrated ictal discharges in 51% of slices and interictal activity in 24.5% (n = 41, p [lt] 0.05, Chi-square). In slices exposed to DHPG and LEV, BMI produced ictal activity in 17% of slices with 32% displaying interictal discharges. Control DHPG-exposed slices demonstrated ictal activity in 39% with 41% having interictal activity (n = 41, p [lt] 0.05). VPA (300[mu]M) did not significantly change the percentage of slices showing either ictal or interictal activity compared to control DHPG-exposed slices (ictal activity in 37% of VPA/DHPG exposed slices compared to 37% of DHPG exposed; interictal activity in 29% in VPA/DHPG exposed slices compared to 39% in slices exposed to DHPG alone, p[gt] 0.05, n = 35 for VPA, n =38 for control). In the presence of BMI, there were no differences in the patterns of epileptiform activity in slices exposed to VPA or control slices. The induction of persistent epileptiform activity by DHPG was blocked significantly by LEV. VPA, another drug that retards kindling did not have any effects on the induction of persistent epileptiform activity that follows DHPG exposure. These results demonstrate an anti-epileptogenic effect of LEV that impairs mechanisms of group I mGluR epileptogenesis. (Supported by UCB Pharma.)