title: Lamotrigine derivatives and riluzole inhibit INa,P in cortical neurons.
abstract: The persistent, slowly inactivating fraction of the sodium current is involved in key functions in the CNS such as dendritic integration of synaptic inputs and cellular excitability. We have studied whether established anti-epileptic drugs and neuroprotective agents target the persistent sodium current. Two lamotrigine derivatives (sipatrigine and 202W92) and riluzole inhibited the persistent sodium current at low, therapeutic concentrations. In contrast, lamotrigine and the classical antiepileptic agents phenytoin and valproic acid blocked the fast-inactivating sodium channel but failed to affect the persistent fraction. The ability to influence either mode of channel activity may represent a defining feature of each drug subclass, changing profoundly their clinical indications. Given the damaging role of a sustained influx of sodium in both pharmaco-resistant seizures or excitotoxic insults, we suggest the utilization of drugs that suppress the persistent conductance.
authors.affiliation: IRCCS Fondazione Santa Lucia, Roma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Spadoni
authors.forename: Atticus Henry
authors.initials: AH
authors.lastname: Hainsworth
authors.forename: Nicola Biagio
authors.initials: NB
authors.lastname: Mercuri
authors.forename: Luigi
authors.initials: L
authors.lastname: Caputi
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Martella
authors.forename: Franco
authors.initials: F
authors.lastname: Lavaroni
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Stefani
mesh_terms: D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D000077213:Lamotrigine; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D019782:Riluzole / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D026941:Sodium Channel Blockers; D015222:Sodium Channels / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology*
chemical_list: C443646:2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)pyrimidine; D000889:Anti-Arrhythmia Agents; D000927:Anticonvulsants; D018696:Neuroprotective Agents; D010879:Piperazines; D011743:Pyrimidines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014227:Triazines; D019782:Riluzole; D012964:Sodium; D000638:Amiodarone; C081980:sipatrigine; D000077213:Lamotrigine