title: Differential effects of lacosamide, phenytoin and topiramate on peripheral nerve excitability: An ex vivo electrophysiological study.
abstract: BACKGROUND
  Antiepileptic drugs (AEDs) are mainly used to control cortical hyperexcitability. Some of them (e.g. phenytoin (PHT) and topiramate (TPM)) have also effects on the peripheral nervous system (PNS). Lacosamide (LCM) is a novel AED that stabilizes hyperexcitable neuronal membranes by selectively enhancing the slow inactivation of voltage-gated sodium channels (VGSCs). Although the mechanism of action of LCM is fairly well understood, there are no in vitro data available regarding any possible PNS effects of LCM.
  
  
  OBJECTIVE
  To investigate, in vitro, the effects of LCM on peripheral nerve excitability in comparison with PHT and TPM, two AEDs that act, in part, by stabilizing the fast inactivation state of VGSCs.
  
  
  METHODS
  Experiments were conducted on the isolated sciatic nerve of the adult rat using standard electrophysiological methods. The effects of LCM on the amplitude and latency of the evoked compound action potential (CAP) during a 48h period of drug exposure were recorded and compared with the effects of PHT and TPM.
  
  
  RESULTS
  LCM produced inhibitory effects on CAP at concentrations significantly higher than the therapeutic levels (>25μg/ml). At these concentrations (62.57-125.15μg/ml), an acute and immediate increment of the latency and decrement of the amplitude of the CAP were observed. In contrast to LCM, PHT caused an acute decrement in the amplitude as well as an increment in the latency of the CAP even at subtherapeutic levels (5μg/ml). With regard to TPM, the amplitude of the CAP was not affected at the supratherapeutic concentrations but at the therapeutic concentration of 33.94μg/ml a reduced decrement of the CAP amplitude compared to the controls was observed.
  
  
  CONCLUSIONS
  LCM, PHT and TPM exert differential effects on peripheral nerve excitability. PHT inhibited the sciatic nerve CAP even at subtherapeutic levels whereas LCM was safe within the therapeutic concentration range. TPM did not affect the CAP amplitude even at high supratherapeutic concentrations whereas in the therapeutic range a neuroprotective effect was observed. Possible underlying mechanisms and the clinical implications of these findings are discussed.
authors.affiliation: Laboratory of Clinical Neurophysiology, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece. Electronic address: gzafeiri@auth.gr.
authors.forename: Georgia
authors.initials: G
authors.lastname: Zafeiridou
authors.affiliation: 1st Department of Neurology, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.
authors.forename: Martha
authors.initials: M
authors.lastname: Spilioti
authors.affiliation: Laboratory of Animal Physiology, Department of Zoology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Alexia
authors.initials: A
authors.lastname: Kagiava
authors.affiliation: DatAnalysis, Statistics and Research Design Company, Dodonis 159, 45221 Ioannina, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Krikonis
authors.affiliation: Laboratory of Physiology, Department of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Efstratios K
authors.initials: EK
authors.lastname: Kosmidis
authors.affiliation: Laboratory of Clinical Neurophysiology, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.
authors.forename: Anna
authors.initials: A
authors.lastname: Karlovasitou
authors.affiliation: Laboratory of Clinical Neurophysiology, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.
authors.forename: Vasilios K
authors.initials: VK
authors.lastname: Kimiskidis
mesh_terms: D000081:Acetamides / Q000009:adverse effects*; D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005260:Female; D005632:Fructose / Q000009:adverse effects / Q000031:analogs & derivatives*; D066298:In Vitro Techniques; D000078334:Lacosamide; D008297:Male; D010672:Phenytoin / Q000009:adverse effects*; D051381:Rats; D012584:Sciatic Nerve / Q000187:drug effects* / Q000502:physiology; D000077236:Topiramate
chemical_list: D000081:Acetamides; D000077236:Topiramate; D005632:Fructose; D000078334:Lacosamide; D010672:Phenytoin
keywords: Antinociception; CAP; Lacosamide; Neurotoxicity; Peripheral nerve excitability; Phenytoin; Topiramate