title: Activity of the anticonvulsant lacosamide in experimental and human epilepsy via selective effects on slow Na+channel inactivation.
abstract: In human epilepsy, pharmacoresistance to antiepileptic drug therapy is a major problem affecting ~30% of patients with epilepsy. Many classical antiepileptic drugs target voltage-gated sodium channels, and their potent activity in inhibiting high-frequency firing has been attributed to their strong use-dependent blocking action. In chronic epilepsy, a loss of use-dependent block has emerged as a potential cellular mechanism of pharmacoresistance for anticonvulsants acting on voltage-gated sodium channels. The anticonvulsant drug lacosamide (LCM) also targets sodium channels, but has been shown to preferentially affect sodium channel slow inactivation processes, in contrast to most other anticonvulsants.
  
  
  
  We used whole-cell voltage clamp recordings in acutely isolated cells to investigate the effects of LCM on transient Na+currents. Furthermore, we used whole-cell current clamp recordings to assess effects on repetitive action potential firing in hippocampal slices.
  
  
  
  We show here that LCM exerts its effects primarily via shifting the slow inactivation voltage dependence to more hyperpolarized potentials in hippocampal dentate granule cells from control and epileptic rats, and from patients with epilepsy. It is important to note that this activity of LCM was maintained in chronic experimental and human epilepsy. Furthermore, we demonstrate that the efficacy of LCM in inhibiting high-frequency firing is undiminished in chronic experimental and human epilepsy.
  
  
  
  Taken together, these results show that LCM exhibits maintained efficacy in chronic epilepsy, in contrast to conventional use-dependent sodium channel blockers such as carbamazepine. They also establish that targeting slow inactivation may be a promising strategy for overcoming target mechanisms of pharmacoresistance.
authors.affiliation: Department of Epileptology, Laboratory for Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Holtkamp
authors.affiliation: Department of Epileptology, Laboratory for Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.
authors.forename: Thoralf
authors.initials: T
authors.lastname: Opitz
authors.affiliation: UCB Pharma, Braine l'Alleud, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Niespodziany
authors.affiliation: UCB Pharma, Braine l'Alleud, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Wolff
authors.affiliation: Department of Epileptology, Laboratory for Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.|German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Beck
mesh_terms: D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use*; D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use*; D001703:Biophysics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D000078334:Lacosamide; D008564:Membrane Potentials / Q000187:drug effects*; D018721:Muscarinic Agonists / Q000633:toxicity; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010862:Pilocarpine / Q000633:toxicity; D017208:Rats, Wistar; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D018721:Muscarinic Agonists; D015222:Sodium Channels; D010862:Pilocarpine; D000078334:Lacosamide
keywords: Anticonvulsant drugs; Epilepsy; Lacosamide; Pharmacoresistance