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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Amiodarone / pharmacology
-
Animals
-
Anti-Arrhythmia Agents / pharmacology
-
Anticonvulsants / pharmacology*
-
Cerebral Cortex / drug effects*
-
Cerebral Cortex / metabolism
-
Cerebral Cortex / physiopathology
-
Dose-Response Relationship, Drug
-
Epilepsy / drug therapy*
-
Epilepsy / metabolism
-
Epilepsy / physiopathology
-
Lamotrigine
-
Male
-
Membrane Potentials / drug effects
-
Membrane Potentials / physiology
-
Neural Inhibition / drug effects*
-
Neural Inhibition / physiology
-
Neuroprotective Agents / pharmacology
-
Piperazines / pharmacology
-
Pyramidal Cells / drug effects*
-
Pyramidal Cells / metabolism
-
Pyrimidines / pharmacology
-
Rats
-
Rats, Wistar
-
Riluzole / pharmacology*
-
Sodium / metabolism
-
Sodium Channel Blockers*
-
Sodium Channels / metabolism
-
Triazines / pharmacology*
Substances
-
2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)pyrimidine
-
Anti-Arrhythmia Agents
-
Anticonvulsants
-
Neuroprotective Agents
-
Piperazines
-
Pyrimidines
-
Sodium Channel Blockers
-
Sodium Channels
-
Triazines
-
Riluzole
-
Sodium
-
Amiodarone
-
sipatrigine
-
Lamotrigine