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Blockade of T-type calcium channels prevents tonic-clonic seizures in a maximal electroshock seizure model

Sophie Sakkaki1, Giuseppe Gangarossa2, Benoit Lerat2

  • 1Université de Montpellier, CNRS UMR 5203, Département Neuroscience & Ion Channel Biology, Institut de Génomique Fonctionnelle, Montpellier F-34094, France; INSERM U1191, Montpellier F34094, France; LabEx 'Ion Channel Science and Therapeutics', Montpellier F34094, France; Sanofi R&D, F-91385 Chilly-Mazarin, France.

Neuropharmacology
|October 13, 2015
PubMed

Insights

TTA-A2, a T-type calcium channel blocker, demonstrates potent anticonvulsant properties against generalized seizures in mice. The Cav3.1 calcium channel isoform is crucial for TTA-A2

Area of Science:

  • Neuroscience
  • Pharmacology
  • Epilepsy Research

Background:

  • T-type (Cav3) calcium channels are implicated in neuronal excitability and epilepsy.
  • Selective blockade of these channels may offer therapeutic benefits for seizure disorders.

Purpose of the Study:

  • To evaluate the anticonvulsant effects of TTA-A2, a selective T-type calcium channel blocker.
  • To investigate the role of Cav3.1 and Cav3.2 isoforms in TTA-A2's anticonvulsant activity.

Main Methods:

  • Maximal electroshock seizure (MES) test in mice to model generalized tonic-clonic seizures.
  • Administration of TTA-A2 and assessment of seizure protection.
  • Analysis of Local Field Potential (LFP) patterns and post-ictal delta frequency power.
  • Evaluation of Cav3.1 and Cav3.2 knockout mouse models.
  • Assessment of ERK phosphorylation and c-Fos expression in the hippocampus.

Main Results:

  • TTA-A2 (≥0.3 mg/kg) significantly protected mice against tonic seizures in the MES test.
  • TTA-A2 treatment increased delta frequency power during the late post-ictal period.
  • Cav3.1 knockout mice showed reduced susceptibility to tonic seizures and TTA-A2 protection.
  • Cav3.2 knockout mice did not exhibit altered seizure susceptibility or TTA-A2 response.
  • Neuronal activation markers (p-ERK, c-Fos) in the hippocampus remained unchanged by TTA-A2 treatment.

Conclusions:

  • TTA-A2 exhibits potent anticonvulsant properties, particularly against generalized tonic-clonic seizures.
  • The Cav3.1 calcium channel isoform plays a significant role in mediating the anticonvulsant effects of TTA-A2.
  • TTA-A2 represents a promising therapeutic agent for epilepsy, with Cav3.1 as a key target.
Keywords:
AnticonvulsantLocal Field PotentialMaximal electroshock seizureT-type voltage-gated calcium channelsTonic-clonic seizure

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