Abstracts

Rationale: Catamenial epilepsy is a form of epilepsy in which seizures are clustered around specific points in the menstrual cycle, most frequently during perimenstrual or periovulatory phase. Perimenstrual catamenial seizure exacerbation has long been known to be associated with an abrupt withdrawal of progesterone. The progesterone’s antiseizure effect is due in part to its conversion to the “neurosteroid” allopregnanolone. Currently there is no specific drug to treat catamenial seizures, which impact at least 1 in 3 women with epilepsy. In this study, we tested the hypothesis that selective augmentation of tonic GABAergic inhibition mediated by delta-subunit containing GABA-A receptors leads to effective inhibition of perimenstrual catamenial seizures. To test this hypothesis, we utilized gaboxedol, which is a systemically active, delta-subunit-preferring GABA-A receptor agonist that enhances tonic GABAergic inhibition in the hippocampus.Methods: We utilized a rat model of catamenial seizure exacerbation that was developed in our lab. This spontaneous model was developed based on the premise that repeated neurosteroid withdrawal leads to “catamenial-like” exacerbation of spontaneous recurrent seizures in epileptic state. A state of chronic epilepsy was induced in female rats by the lithium-pilocarpine protocol. Rats were monitored for the occurrence of SRS and electrographic (EEG) seizure events during 2-6 months post pilocarpine. To model catamenial seizure exacerbation, epileptic rats were subjected to repeated neurosteroid withdrawal by a pseudopregnancy-finasteride paradigm. The efficacy of gaboxedol (5 mg/kg, sc) was evaluated during the withdrawal period. Four key parameters were recorded including: (a) frequency and duration of spontaneous seizures; (b) frequency and duration of electrographic seizures; (c) frequency of interictal spikes; and (d) percent time in EEG seizures. The mossy fiber sprouting and hippocampal interneuron damage was assessed as morphological indices of epileptogenesis. Results: Pilocarpine treatment was associated with spontaneous recurrent seizures after latency of 60 days post pilocarpine. Neurosteroid withdrawal in epilepsy rats was associated with significant exacerbation of severity and frequency of spontaneous seizures, including exacerbation of electrographic events. The average seizure frequency was 2 seizures daily, which was increased to 4 seizures daily during the withdrawal period. Gaboxedol therapy significantly decreased the frequency and duration of spontaneous seizures as well as EEG electrographic events. Conclusions: These results reveal that neurosteroid withdrawal in epileptic rats leads to heightened spontaneous recurrent seizures, which may represent a suitable animal model of perimenstrual catamenial epilepsy. These key seizure parameters were markedly reduced by gaboxedol treatment, confirming the efficacy of tonic GABAergic inhibition as an effective strategy for catamenial epilepsy therapy. ** Supported partly by NIH grant NS052158 **