title: Ranolazine vs phenytoin: greater effect of ranolazine on the transient Na(+) current than on the persistent Na(+) current in central neurons.
abstract: Voltage-gated Na(+) channels (NaV) are involved in pathologies and are important targets of drugs (NaV-blockers), e.g. some anti-epileptic drugs (AEDs). Besides the fast inactivating transient Na(+) current (INaT), they generate a slowly inactivating "persistent" current (INaP). Ranolazine, a NaV-blocker approved for treatment of angina pectoris, is considered a preferential inhibitor of INaP and has been proposed as a novel AED. Although it is thought that classic NaV-blockers used as AEDs target mainly INaT, they can also reduce INaP. It is important to disclose specific features of novel NaV-blockers, which could be necessary for their effect as AEDs in drug resistant patients. We have compared the action of ranolazine and of the classic AED phenytoin in transfected cells expressing the neuronal NaV1.1 Na(+) channel and in neurons of neocortical slices. Our results show that the relative block of INaT versus INaP of ranolazine and phenytoin is variable and depends on Na(+) current activation conditions. Strikingly, ranolazine blocks with less efficacy INaP and more efficacy INaT than phenytoin in conditions mimicking pathological states (i.e. high frequency firing and long lasting depolarizations). The effects are consistent with binding of ranolazine to both open/pre-open and inactivated states; larger INaT block at high stimulation frequencies is caused by the induction of a slow inactivated state. Thus, contrary than expected, ranolazine is not a better INaP blocker than phenytoin in central neurons, and phenytoin is not a better INaT blocker than ranolazine. Nevertheless, they show a complementary action and could differentially target specific pathological dysfunctions.
authors.affiliation: Department of Neurophysiology and Diagnostic Epileptology, IRCCS Foundation C. Besta Neurological Institute, 20133, Milan, Italy. Electronic address: benedetta.terragni@istituto-besta.it.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Terragni
authors.affiliation: Department of Neurophysiology and Diagnostic Epileptology, IRCCS Foundation C. Besta Neurological Institute, 20133, Milan, Italy. Electronic address: paolo.scalmani@istituto-besta.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Scalmani
authors.affiliation: Department of Neurophysiology and Diagnostic Epileptology, IRCCS Foundation C. Besta Neurological Institute, 20133, Milan, Italy. Electronic address: elisacolombo77@gmail.com.
authors.forename: Elisa
authors.initials: E
authors.lastname: Colombo
authors.affiliation: Department of Neurophysiology and Diagnostic Epileptology, IRCCS Foundation C. Besta Neurological Institute, 20133, Milan, Italy. Electronic address: silvana.franceschetti@istituto-besta.it.
authors.forename: Silvana
authors.initials: S
authors.lastname: Franceschetti
authors.affiliation: Institute of Molecular and Cellular Pharmacology (IPMC), CNRS UMR7275, 06560, Valbonne-Sophia Antipolis, France; University of the Côte d'Azur (UCA), 06560, Valbonne-Sophia Antipolis, France; Inserm, 06560, Valbonne-Sophia Antipolis, France. Electronic address: mantegazza@ipmc.cnrs.fr.
authors.forename: Massimo
authors.initials: M
authors.lastname: Mantegazza
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002414:Cations, Monovalent / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010672:Phenytoin / Q000494:pharmacology*; D000069458:Ranolazine / Q000494:pharmacology*; D066191:Sensorimotor Cortex / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D046509:Tissue Culture Techniques; D014162:Transfection
chemical_list: D002414:Cations, Monovalent; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D010672:Phenytoin; D012964:Sodium; D000069458:Ranolazine
keywords: Antiepileptic drugs; Patch-clamp; Persistent current; Phenytoin; Ranolazine; Voltage-gated Na(+) channels