Lamotrigine derivatives and riluzole inhibit INa,P in cortical neurons.
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.
Spadoni
Francesca
F
IRCCS Fondazione Santa Lucia, Roma, Italy.
Hainsworth
Atticus Henry
AH
Mercuri
Nicola Biagio
NB
Caputi
Luigi
L
Martella
Giuseppina
G
Lavaroni
Franco
F
Bernardi
Giorgio
G
Stefani
Alessandro
A
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*
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