Abstracts

Rationale: We developed a Stimulation Train Induced Bursting (STIB) model using fresh rat hippocampal slices, where epileptic-like discharges are acutely induced by repeated electrical stimulations, similar to electrical kindling in vivo. The STIB model in hippocampal slices, considered as an acute model of ictogenesis and epileptogenesis, is a convenient tool for studying epileptic signals and of their modulation in neuronal circuits. In this model, repeated high-frequency electrical stimulations (HFS) induce the progressive development of ictal-like afterdischarges (ADs) resembling ictal discharges observed in human temporal lobe epilepsy. In the present study, the STIB model was used to evaluate the efficacy of different classes of antiepileptic drugs (AEDs) at reducing the ictogenesis previously induced.Methods: Induction and development of ADs was performed in CA1 hippocampal area with a HFS (2 sec at 60Hz) repeatedly applied on Schaffer collaterals every 5 min for 80 min. The time-course of AD parameters (duration, number and amplitude of individual bursts within AD and coastline bursting index) was measured and compared between drug-treated and time-matched control groups of slices. AEDs with different modes of action were tested: carbamazepine, phenytoin and lacosamide (Nav channel blockers); levetiracetam (SV2A ligand); clonazepam (GABA-A enhancer); retigabine (M-channel enhancer); perampanel (AMPA negative allosteric modulator).Results: We observed that except for levetiracetam, all tested AEDs reduced AD intensity, but were not able to suppress it completely, suggesting some degree of pharmacoresistance. Clonazepam attenuated the AD development by slightly altering its duration and amplitude. Retigabine prevented the full AD development by strongly decreasing the burst number. Levetiracetam did not modify AD parameters. Perampanel induced an overall concentration-dependent reduction of all AD parameters. Finally, AEDs acting through Na+ channels blockade mainly reduced the burst number and suppressed tonic-like bursts.Conclusions: The STIB model allowed the establishment of specific AEDs signatures, according to their efficacy at reducing specific AD parameters. This model offers an opportunity to differentiate and compare novel AEDs, alone or combination, in terms of their efficacy and mode of action. UCB Pharma-sponsored