title: Eslicarbazepine and the enhancement of slow inactivation of voltage-gated sodium channels: a comparison with carbamazepine, oxcarbazepine and lacosamide.
abstract: This study aimed at evaluating the effects of eslicarbazepine, carbamazepine (CBZ), oxcarbazepine (OXC) and lacosamide (LCM) on the fast and slow inactivated states of voltage-gated sodium channels (VGSC). The anti-epileptiform activity was evaluated in mouse isolated hippocampal slices. The anticonvulsant effects were evaluated in MES and the 6-Hz psychomotor tests. The whole-cell patch-clamp technique was used to investigate the effects of eslicarbazepine, CBZ, OXC and LCM on sodium channels endogenously expressed in N1E-115 mouse neuroblastoma cells. CBZ and eslicarbazepine exhibit similar concentration dependent suppression of epileptiform activity in hippocampal slices. In N1E-115 mouse neuroblastoma cells, at a concentration of 250 μM, the voltage dependence of the fast inactivation was not influenced by eslicarbazepine, whereas LCM, CBZ and OXC shifted the V0.5 value (mV) by -4.8, -12.0 and -16.6, respectively. Eslicarbazepine- and LCM-treated fast-inactivated channels recovered similarly to control conditions, whereas CBZ- and OXC-treated channels required longer pulses to recover. CBZ, eslicarbazepine and LCM shifted the voltage dependence of the slow inactivation (V0.5, mV) by -4.6, -31.2 and -53.3, respectively. For eslicarbazepine, LCM, CBZ and OXC, the affinity to the slow inactivated state was 5.9, 10.4, 1.7 and 1.8 times higher than to the channels in the resting state, respectively. In conclusion, eslicarbazepine did not share with CBZ and OXC the ability to alter fast inactivation of VGSC. Both eslicarbazepine and LCM reduce VGSC availability through enhancement of slow inactivation, but LCM demonstrated higher interaction with VGSC in the resting state and with fast inactivation gating.
authors.affiliation: B'SYS GmbH Analytics, Witterswil, Switzerland.
authors.forename: Simon
authors.initials: S
authors.lastname: Hebeisen
authors.affiliation: BIAL - Portela & C(a), S.A., S. Mamede do Coronado, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Pires
authors.affiliation: BIAL - Portela & C(a), S.A., S. Mamede do Coronado, Portugal.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Loureiro
authors.affiliation: BIAL - Portela & C(a), S.A., S. Mamede do Coronado, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Bonifácio
authors.affiliation: BIAL - Portela & C(a), S.A., S. Mamede do Coronado, Portugal.
authors.forename: Nuno
authors.initials: N
authors.lastname: Palma
authors.affiliation: Neurosolutions Ltd, Coventry CV4 7ZS, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Whyment
authors.affiliation: Neurosolutions Ltd, Coventry CV4 7ZS, UK; Department of Physiology, Monash University, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Spanswick
authors.affiliation: BIAL - Portela & C(a), S.A., S. Mamede do Coronado, Portugal; Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Portugal; MedInUP - Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal. Electronic address: pss@med.up.pt.
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003984:Dibenzazepines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D000078334:Lacosamide; D008297:Male; D051379:Mice; D009924:Organ Culture Techniques; D000078330:Oxcarbazepine; D013997:Time Factors; D061566:Voltage-Gated Sodium Channels / Q000502:physiology*
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D003984:Dibenzazepines; D061566:Voltage-Gated Sodium Channels; D002220:Carbamazepine; D000078334:Lacosamide; C571001:eslicarbazepine; D000078330:Oxcarbazepine
keywords: Carbamazepine; Eslicarbazepine; Fast inactivation; Lacosamide; Oxcarbazepine; Slow inactivation; Voltage-gated sodium channel