Treatment of status epilepticus

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Status epilepticus is a neurological emergency characterized by very prolonged, sometimes refractory seizures, and is associated with a 23% mortality. Benzodiazepines are the drugs of choice for the initial treatment of status epilepticus. Randomized double-blind placebo-controlled clinical trials demonstrated that benzodiazepines effectively control acute recurrent seizures and brief (5-15 minute) status epilepticus in the out-of-hospital settings. Other hospital based randomized clinical trials have demonstrated that benzodiazepines effectively control acute convulsive status epilepticus. Despite their efficacy in early stages of status epilepticus, benzodiazepines can fail. In one randomized, double-blind clinical trial of prolonged subtle status epilepticus, benzodiazepines were largely ineffective and controlled seizures in fewer than 20% of patients. [unreadable] [unreadable] In experimental animals diazepam controlled brief seizures but failed after prolonged status epilepticus. GABA-mediated miniature inhibitory postsynaptic currents (mlPSCs) were recorded from dentate granule cells of na?ve animals as well as animals that have undergone 60 minutes of self-sustaining status epilepticus, mlPSCs recorded from status epilepticus-treated animals were smaller in amplitude and slower in decay than those recorded from controls. Other experiments revealed that mIPSCs recorded from granule cells of control animals were robustly enhanced by 30 nM diazepam, but those recorded from granule cells of status epilepticus-treated animals were not enhanced by 30 nM diazepam. In naive rat dentate granule cells, the diazepam-sensitive a1 and ?2 subunit-containing GABAA receptors are present at GABAergic synapses. The diazepam-insensitive, a4 and d subunit-containing receptors are expressed in dentate granule cells of na?ve rats and were demonstrated to be extrasynaptic. These considerations lead us to formulate the hypothesis that refractoriness to benzodiazepines during status epilepticus is associated with the shift of the a4 and d subunit-containing receptors from the extrasynaptic to the synaptic location and a reduction of a1 and ?2subunit-containing receptors in the synapses. [unreadable] [unreadable] Experiments are proposed to accomplish the following specific aims: 1) To compare the subunitsensitive properties of mlPSCs recorded from dentate granule cells of control animals and from animals in early and refractory status epilepticus by means of patch clamp recordings and 2) To characterize the site of expression of specific GABAA receptor subunits (a1, a4, ?2, and d) on dentate granule cells in control rats and those in early and refractory status epilepticus by double label immunohistochemistry studies combined with confocal laser microscopy and post-embedding immunogold electron microscopy. Significance: These studies will provide insights into mechanisms of resistance to benzodiazepines during status epilepticus and they will improve our understanding of the effect of status epilepticus on GABAergic synaptic transmission. [unreadable] [unreadable]