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Article
Current Understanding of the Mechanism of Action of the Antiepileptic Drug Lacosamide
Epilepsy Research (2015)
  • Michael A. Rogawski, University of California - Davis
  • Azita Tofighy
  • H Steve White, University of Utah
  • Alain Matagne
  • Christian Wolff
Abstract
The antiepileptic drug lacosamide [(R)-2-acetamido-N-benzyl-3-methoxypropanamide], a chiral functionalized amino acid, was originally identified by virtue of activity in the mouse and rat maximal electroshock (MES) test. Attention was drawn to lacosamide because of its high oral potency and stereoselectivity. Lacosamide is also active in the 6 Hz seizure model but inactive against clonic seizures in rodents induced by subcutaneous pentylenetetrazol, bicuculline and picrotoxin. It is also ineffective in genetic models of absence epilepsy. At doses greater than those required to confer protection in the MES test, lacosamide inhibits behavioral and electrographic seizures in hippocampal kindled rats. It also effectively terminates seizures in the rat perforant path stimulation status epilepticus model when administered early after the onset of seizures. Lacosamide does not exhibit antiepileptogenic effects in kindling or post-status epilepticus models. The profile of lacosamide in animal seizure and epilepsy models is similar to that of sodium channel blocking antiepileptic drugs, such as phenytoin and carbamazepine. However, unlike these agents, lacosamide does not affect sustained repetitive firing (SRF) on a time scale of hundreds of milliseconds or affect fast inactivation of voltage-gated sodium channels; however, it terminates SRF on a time scale of seconds by an apparent effect on sodium channel slow inactivation. Lacosamide shifts the slow inactivation curve to more hyperpolarized potentials and enhances the maximal fraction of channels that are in the slow inactivated state. Currently, lacosamide is the only known antiepileptic drug in clinical practice that exerts its anticonvulsant activity predominantly by selectively enhancing slow sodium channel inactivation.
Keywords
  • lacosamide,
  • voltage-gated sodium channel
Publication Date
December, 2015
Publisher Statement
Available at: http://dx.doi.org/10.1016/j.eplepsyres.2014.11.021
Citation Information
Michael A. Rogawski, Azita Tofighy, H Steve White, Alain Matagne, et al.. "Current Understanding of the Mechanism of Action of the Antiepileptic Drug Lacosamide" Epilepsy Research Vol. 110 (2015)
Available at: http://works.bepress.com/michael_rogawski/70/