title: Blockade of T-type calcium channels prevents tonic-clonic seizures in a maximal electroshock seizure model.
abstract: T-type (Cav3) calcium channels play important roles in neuronal excitability, both in normal and pathological activities of the brain. In particular, they contribute to hyper-excitability disorders such as epilepsy. Here we have characterized the anticonvulsant properties of TTA-A2, a selective T-type channel blocker, in mouse. Using the maximal electroshock seizure (MES) as a model of tonic-clonic generalized seizures, we report that mice treated with TTA-A2 (0.3 mg/kg and higher doses) were significantly protected against tonic seizures. Although no major change in Local Field Potential (LFP) pattern was observed during the MES seizure, analysis of the late post-ictal period revealed a significant increase in the delta frequency power in animals treated with TTA-A2. Similar results were obtained for Cav3.1-/- mice, which were less prone to develop tonic seizures in the MES test, but not for Cav3.2-/- mice. Analysis of extracellular signal-regulated kinase 1/2 (ERK) phosphorylation and c-Fos expression revealed a rapid and elevated neuronal activation in the hippocampus following MES clonic seizures, which was unchanged in TTA-A2 treated animals. Overall, our data indicate that TTA-A2 is a potent anticonvulsant and that the Cav3.1 isoform plays a prominent role in mediating TTA-A2 tonic seizure protection.
authors.affiliation: Université 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.
authors.forename: Sophie
authors.initials: S
authors.lastname: Sakkaki
authors.affiliation: Université de Montpellier, CNRS UMR 5203, Département Neuroscience & Ion Channel Biology, Institut de Génomique Fonctionnelle, Montpellier F-34094, France; INSERM U1191, Montpellier F34094, France.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Gangarossa
authors.affiliation: Université de Montpellier, CNRS UMR 5203, Département Neuroscience & Ion Channel Biology, Institut de Génomique Fonctionnelle, Montpellier F-34094, France; INSERM U1191, Montpellier F34094, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Lerat
authors.affiliation: Sanofi R&D, F-91385 Chilly-Mazarin, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Françon
authors.affiliation: Université de Montpellier, CNRS UMR 5203, Département Neuroscience & Ion Channel Biology, Institut de Génomique Fonctionnelle, Montpellier F-34094, France; INSERM U1191, Montpellier F34094, France.
authors.forename: Luc
authors.initials: L
authors.lastname: Forichon
authors.affiliation: Université 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.
authors.forename: Jean
authors.initials: J
authors.lastname: Chemin
authors.affiliation: Université de Montpellier, CNRS UMR 5203, Département Neuroscience & Ion Channel Biology, Institut de Génomique Fonctionnelle, Montpellier F-34094, France; INSERM U1191, Montpellier F34094, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Valjent
authors.affiliation: Université de Montpellier, CNRS UMR 5203, Département Neuroscience & Ion Channel Biology, Institut de Génomique Fonctionnelle, Montpellier F-34094, France; INSERM U1191, Montpellier F34094, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Lerner-Natoli
authors.affiliation: Université 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. Electronic address: philippe.lory@igf.cnrs.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Lory
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D044482:Benzeneacetamides / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism*; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004597:Electroshock / Q000009:adverse effects; D005071:Evoked Potentials / Q000187:drug effects / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010433:Pentylenetetrazole / Q000633:toxicity; D011725:Pyridines / Q000627:therapeutic use*; D012640:Seizures / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
chemical_list: C553486:2-(4-cyclopropylphenyl)-N-(1-(5-((2,2,2-trifluoroethyl)oxo)pyridin-2-yl)ethyl)acetamide; D044482:Benzeneacetamides; C498197:Cacna1g protein, mouse; C504883:Cacna1h protein, mouse; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D003292:Convulsants; D011725:Pyridines; D048049:Extracellular Signal-Regulated MAP Kinases; D010433:Pentylenetetrazole
keywords: Anticonvulsant; Local Field Potential; Maximal electroshock seizure; T-type voltage-gated calcium channels; Tonic-clonic seizure