Carbamazepine and Topiramate Modulation of Transient and Persistent Sodium Currents Studied in HEK293 Cells Expressing the Nav1.3 α–Subunit

• Published in: Epilepsia (Copenhagen) Vol. 48; no. 4; pp. 774 - 782
• Main Authors: Sun, Guang‐chun, Werkman, Taco R., Battefeld, Arne, Clare, Jeffrey J., Wadman, Wytse J.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.04.2007; Blackwell
• Subjects: Anticonvulsants. Antiepileptics. Antiparkinson agents; Antiepileptic drug; Biological and medical sciences; Drug toxicity and drugs side effects treatment; Epilepsy; Headache. Facial pains. Syncopes. Epilepsia. Intracranial hypertension. Brain oedema. Cerebral palsy; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Na+ channel NaV1.3; Nervous system (semeiology, syndromes); Neurology; Neuropharmacology; Persistent Na+ current; Pharmacology. Drug treatments; Stable expression system; Whole‐cell voltage clamp; Topiramate; Nervous system diseases; Epilepsy; Anticonvulsant; Ionic current; Tricyclic compound; Subunit; Carbamazepine; Cerebral disorder; Transients; Mood stabilizer; Modulation; Central nervous system disease; Voltage; Dibenzazepine derivatives; Epilepsy-Persistent Na+ current-Whole- cell voltage clamp-Na+ channel Nav1.3-Stable expression system-Antiepileptic drug
• ISSN: 0013-9580; 1528-1167
• DOI: 10.1111/j.1528-1167.2007.01001.x

Purpose: The transient and the persistent Na+ current play a distinct role in neuronal excitability. Several antiepileptic drugs (AEDs) modulate the transient Na+ current and block the persistent Na+ current; both effects contribute to their antiepileptic properties. The interactions of the AEDs carbamazepine (CBZ) and topiramate (TPM) with the persistent and transient Na+ current were investigated. Methods: HEK293 cells stably expressing the α‐subunit of the Na+ channel NaV1.3 were used to record Na+ currents under voltage‐clamp by using the patch‐clamp technique in whole‐cell configuration and to investigate the effects of CBZ and TPM. Results: The persistent Na+ current was present in all cells and constituted 10.3 ± 3.8% of the total current. CBZ partially blocked the persistent Na+ current in a concentration‐dependent manner [median effective concentration (EC50), 16 ± 4 μM]. CBZ also shifted the steady‐state inactivation of the transient Na+ current to negative potentials (EC50, 14 ± 11 μM). TPM partially blocked the persistent Na+ current with a much higher affinity (EC50, 61 ± 37 nM) than it affected the steady‐state inactivation of the transient Na+ current (EC50, 3.2 ± 1.8 μM). For the latter effect, TPM was at most half as effective as CBZ. Conclusions: The persistent Na+ current flowing through the α‐subunit of the NaV1.3 channel is partially blocked by CBZ at about the same therapeutic concentrations at which it modulates the transient Na+ current, adding a distinct aspect to its anticonvulsant profile. The TPM‐induced partial block of the persistent Na+ current, already effective at low concentrations, could be the dominant action of this drug on the Na+ current.