Abstracts

Rationale: Neuroactive steroids are a class of compounds that can directly bind and potentiate neurotransmitter receptors in the brain. Some endogenous neuroactive steroids, such as allopregnanolone, potentiate GABAA receptors through allosteric modulation, and demonstrate anticonvulsant properties. SAGE-217 is a proprietary synthetic neurosteroid developed to potentiate GABAA receptors with improved potency and bioavailability. SAGE-217 is anticonvulsant in multiple acute seizure assays in rodents. Here we examined the anticonvulsant activity of SAGE-217 in a mouse model of chronic medial temporal lobe epilepsy (MTLE), a condition which affects an estimated 10% of the total epileptic population.Methods: Adult mice (C57/Bl6, n=8) were unilaterally administered 1 nM kainate in the right hippocampus and implanted with a bipolar electrode. Epileptogensis developed over 4 weeks. Hippocampal paroxysmal discharges (HPDs) are defined as sequence of high voltage sharp waves followed by a sequence of lower voltage and higher frequency spikes-and-waves lasting at least 5s and separated by at least 1s. MTLE mice were injected with drugs in a random order (one injection per week) using a Latin square design. EEG recordings were performed on freely moving animals for 20 minutes pre-injection (baseline period) and 10 to 130 minutes post-injection.Results: SAGE-217 (1, 3 and 5 mg/kg, IP) significantly suppressed the number and cumulated duration of HPDs in a dose dependent manner. SAGE-217 reduced HPDs by >90% between 10 and 70 minutes after the 3 mg/kg and over the entire two hour recording period after the 5 mg/kg dose. These effects were superior to the effect of diazepam (2 mg/kg, IP), which reduced HPDs by 84% between 10 and 70 minutes after administration, and only 45% over the subsequent 60 minutes.Conclusions: This study provides the first evidence of neurosteroid efficacy in a mouse model of MTLE and supports developing SAGE-217 and other compounds of this class as novel antiepileptic drugs.