Abstracts

Rationale: Novel therapies are desperately needed for refractory status epilepticus (SE), which is characterized by persistent seizures, progressive internalization of synaptic gamma2-subunit containing GABA-A receptors, reduced phasic inhibition and benzodiazepine resistance. Here we sought to determine the efficacy of natural and synthetic neurosteroids that increase phasic and tonic inhibition in the hippocampus for the control of refractory SE in rats. Methods: Persistent SE was induced chemically by lithium-pilocarpine in adult rats, and neurosteroids were administered subcutaneously at 10 min (early therapy) or 60 min (late therapy) after the onset of SE. The onset and termination of SE was determined by behavioral seizures and EEG recordings from the hippocampus and the cortex for 15 h. Histology was assessed at 72 h after SE. Results: Control animals exhibited electrographic and behavioral SE for over 3 h, which represent a state of refractory SE. Allopregnanolone and related neurosteroids produced effective and complete termination of electrographic and behavioral SE when administered early and late after SE onset. With late therapy, neurosteroids aborted seizures with very little seizure recurrences, a profile that was superior to diazepam. In addition, neurosteroid therapy conferred neuroprotection by diminishing the neuronal cell death and neurodegeneration associated with SE. Structure-activity relation (SAR) studies showed that neurosteroid analogs with the 3-OH in the ?-position and 5-H in the a-configuration were highly effective termination of seizure activity. Neurosteroids with 17b-methyl-carbonyl group are more potent than corresponding analogs with 17b-hydroxyl group. Conclusions: Neurosteroids appears to be efficacious in persistent SE induced by cholinergic stimulation, suggesting the possibility that activation of extrasynaptic GABA-A receptors with neurosteroids may be an effective new treatment for refractory SE. Funding: Supported by NIH grants NS071597, NS076426 & NS083460.