Abstracts

Rationale: Clinical evidence has long shown that progesterone exhibits anticonvulsant effects. Unlike many other anticonvulsant drugs, progesterone is endogenous, making it desirable in control of epileptic seizures. It is generally believed that progesterone acts by enhancing the activity of GABAa receptors. Experimental studies, however, suggest that progesterone can affect other receptors /channels. Moreover, metabolites of progesterone have also been shown to possess anticonvulsant effects in animal models. Therefore, the aim of our present study is to explore the effects of progesterone and its metabolites on in vitro epileptiform activities in both GABAa receptor dependent and independent mechanisms. Methods: Horizontal brain slices (0.5mm thick) were obtained from young adult male mice. The slices were perfused with a standard ACSF in a submerged chamber at 35°C. Extracellular recordings were made from entorhinal cortical areas. 4-aminopyridine (100μM), picrotoxin (100μM) and progesterone (100 nM) were added to the ACSF at desired concentrations. Results: Prior to adding 4-AP and PTX, the slices showed stable synaptic field potentials following afferent stimulation, and no epileptiform potentials were recognizable under basal conditions. Upon perfusion of 4-AP and PTX, repetitive epileptiform field potentials similar tor interictal discharges were observed, with durations of 300-500 ms and incidences of 2-5s. These epileptiform field potentials were sensitive to suppression by phenytoin (50μM, n=4). The application of progesterone did not abolish these epileptiform potentials nor significantly alter their amplitude and incidence. Of 10 slices in which progesterone effects were reliably assessed, 8 were shown to have a decrease in area of the epileptiform field potentials (p=0.035, paired test test). Such suppression by progesterone was reversible upon washing. Conclusions: Our pilot data suggest that progesterone can inhibit epileptiform activity in the entorhinal cortex via GABAa receptor-independent actions. Works are in progression to examine the concentration-dependence of progesterone, effects of progesterone in the absence of GABAa antagonists, and the role of metabolites in suppressing epileptiform activity.