title: Diphenytoin, riluzole and lidocaine: three sodium channel blockers, with different mechanisms of action, decrease hippocampal epileptiform activity.
abstract: Epilepsy is a condition affecting 1-2% of the population, characterized by the presence of spontaneous, recurrent seizures. The most common type of acquired epilepsy is temporal lobe epilepsy (TLE). Up to 30% of patients with TLE are refractory to currently available compounds, and there is an urgent need to identify novel targets for therapy. Here, we utilized the in-vitro CA3 burst preparation to examine alterations in network excitability, characterized by changes in interburst interval. Specifically, we show that bath application of three different sodium channel blockers-diphenytoin, riluzole, and lidocaine-slow spontaneous CA3 bursts. This in turn, decreased the epileptiform activity. These compounds work at different sites on voltage-gated sodium channels, but produce a similar network phenotype of decreased excitability. In the case of diphenytoin and riluzole, the change in network activity (i.e., increased interburst intervals) was persistent following drug washout. Lidocaine application, however, only increased the CA3 interburst interval when it was in the bath solution. Thus, its action was not permanent and resulted in returning CA3 bursting to baseline levels. These data demonstrate that the CA3 burst preparation provides a relatively easy and quick platform for identifying compounds that can decrease network excitability, providing the initial screen for further and more complex in-vivo, freely-behaving animal studies.
authors.affiliation: University of Colorado Anschutz Medical Campus, Mailstop 8105, PO Box 6511, Aurora, CO 80045, USA.
authors.forename: Lihong
authors.initials: L
authors.lastname: Diao
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hellier
authors.forename: Jessica
authors.initials: J
authors.lastname: Uskert-Newsom
authors.forename: Philip A
authors.initials: PA
authors.lastname: Williams
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Staley
authors.forename: Audrey S
authors.initials: AS
authors.lastname: Yee
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D056654:CA3 Region, Hippocampal / Q000187:drug effects* / Q000502:physiology; D004558:Electric Stimulation; D005071:Evoked Potentials / Q000187:drug effects* / Q000502:physiology; D008012:Lidocaine / Q000494:pharmacology*; D008297:Male; D010672:Phenytoin / Q000494:pharmacology*; D051381:Rats; D019782:Riluzole / Q000494:pharmacology*; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology*
chemical_list: D061567:Voltage-Gated Sodium Channel Blockers; D010672:Phenytoin; D019782:Riluzole; D008012:Lidocaine
keywords: CA3; Diphenytoin; Epilepsy; Hyperexcitability; Lidocaine; Riluzole