Diphenytoin, riluzole and lidocaine: Three sodium channel blockers, with different mechanisms of action, decrease hippocampal epileptiform activity

• Published in: Neuropharmacology 2013-10, Vol.73, p.48-55
• Main Authors: Diao, Lihong, Hellier, Jennifer L., Uskert-Newsom, Jessica, Williams, Philip A., Staley, Kevin J., Yee, Audrey S.
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Animals; CA3; CA3 Region, Hippocampal - drug effects; CA3 Region, Hippocampal - physiology; Data processing; Diphenytoin; Electric Stimulation; Epilepsy; Evoked Potentials - drug effects; Evoked Potentials - physiology; Hyperexcitability; Lidocaine; Lidocaine - pharmacology; Male; Phenytoin - pharmacology; Rats; Riluzole; Riluzole - pharmacology; Voltage-Gated Sodium Channel Blockers - pharmacology
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.04.057

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. •Three different Na+-channel blockers decrease network CA3 bursting.•Diphenytoin persistently slows spontaneous CA3 bursts.•Riluzole persistently slows spontaneous CA3 bursts.•Lidocaine transiently slows spontaneous CA3 bursts.