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Research ArticleArticle

Inhibition of Transient and Persistent Na+ Current Fractions by the New Anticonvulsant Topiramate

S. Taverna, G. Sancini, M. Mantegazza, S. Franceschetti and G. Avanzini
Journal of Pharmacology and Experimental Therapeutics March 1999, 288 (3) 960-968;
S. Taverna
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G. Sancini
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M. Mantegazza
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S. Franceschetti
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G. Avanzini
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Abstract

The actions of the antiepileptic drug topiramate (TPM) on Na+ currents were assessed using whole-cell patch-clamp recordings in dissociated neocortical neurons and intracellular recordings in neocortical slices. Relatively low TPM concentrations (25–30 μM) slightly inhibited the persistent fraction of Na+ current in dissociated neurons and reduced the Na+-dependent long-lasting action potential shoulders, which can be evoked in layer V pyramidal neurons after Ca++and K+ current blockade. Conversely, the same drug concentrations were ineffective in reducing the amplitude of the fast Na+-dependent action potentials evoked in slices or the peak of transient Na+ (INaf) current evoked in isolated neurons from a physiological holding potential. Consistent INaf inhibition became, however, evident only when the neuronal membrane was kept depolarized to enhance resting Na+ channel inactivation. TPM (100 μM) was ineffective on the voltage dependence of activation but induced a leftward shift of the steady-state INaf inactivation curve. The drug-induced inhibitory effect increased with the duration of membrane depolarization, and the recovery of INaf after long membrane depolarizations was slightly delayed in comparison with that observed under control conditions. The obtained evidence suggests that the anticonvulsant action of TPM may operate by stabilizing channel inactivation, which can be induced by depolarizing events similar to those occurring in chronic epileptic conditions. Concurrently, the slight but significant inhibition of the persistent fraction of the Na+ current, obtained with the application of relatively low TPM concentrations, may contribute toward its anticonvulsant effectiveness by modulating the near-threshold depolarizing events that are sustained by this small current fraction.

Footnotes

  • Send reprint requests to: Dr. Silvana Franceschetti, Istituto Neurologico C. Besta, Department of Neurophysiology, via Celoria 11, 20133 Milano, Italy. E-mail:franceschetti{at}istituto-besta.it

  • Abbreviations:
    INaf
    transient sodium current
    INaP
    persistent sodium current
    TPM
    topiramate
    ACSF
    artificial cerebrospinal fluid
    AP
    action potential
    TTX
    tetrodotoxin
    • Received May 29, 1998.
    • Accepted September 29, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 288 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 288, Issue 3
1 Mar 1999
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Research ArticleArticle

Inhibition of Transient and Persistent Na+ Current Fractions by the New Anticonvulsant Topiramate

S. Taverna, G. Sancini, M. Mantegazza, S. Franceschetti and G. Avanzini
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 960-968;

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Research ArticleArticle

Inhibition of Transient and Persistent Na+ Current Fractions by the New Anticonvulsant Topiramate

S. Taverna, G. Sancini, M. Mantegazza, S. Franceschetti and G. Avanzini
Journal of Pharmacology and Experimental Therapeutics March 1, 1999, 288 (3) 960-968;
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