clozapine and Epilepsies--Partial

Focal epilepsy is commonly pharmacoresistant, and resective surgery is often contraindicated by proximity to eloquent cortex. Many patients have no effective treatment options. Gene therapy allows cell-type specific inhibition of neuronal excitability, but on-demand seizure suppression has only been achieved with optogenetics, which requires invasive light delivery. Here we test a combined chemical-genetic approach to achieve localized suppression of neuronal excitability in a seizure focus, using viral expression of the modified muscarinic receptor hM4Di. hM4Di has no effect in the absence of its selective, normally inactive and orally bioavailable agonist clozapine-N-oxide (CNO). Systemic administration of CNO suppresses focal seizures evoked by two different chemoconvulsants, pilocarpine and picrotoxin. CNO also has a robust anti-seizure effect in a chronic model of focal neocortical epilepsy. Chemical-genetic seizure attenuation holds promise as a novel approach to treat intractable focal epilepsy while minimizing disruption of normal circuit function in untransduced brain regions or in the absence of the specific ligand.

Topics: Acute Disease; Animals; Clozapine; Epilepsies, Partial; Gene Silencing; Genetic Therapy; Humans; Male; Motor Activity; Neocortex; Picrotoxin; Pilocarpine; Rats, Sprague-Dawley; Receptor, Muscarinic M4; Synaptic Transmission

Topics: Clozapine; Dominance, Cerebral; Dose-Response Relationship, Drug; Dystonia; Epilepsies, Partial; Female; Humans; Middle Aged; Treatment Outcome