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Effects of Levetiracetam, Carbamazepine, Phenytoin, Valproate, Lamotrigine, Oxcarbazepine, Topiramate, Vinpocetine and Sertraline on Presynaptic Hippocampal Na+ and Ca2+ Channels Permeability

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Abstract

Ion channels are targets of various antiepileptic drugs. In cerebral presynaptic nerve endings Na+ and Ca2+ channels are particularly abundant, as they control neurotransmitter release, including the release of glutamate (Glu), the most concentrated excitatory amino acid neurotransmitter in the brain. Several pre-synaptic channels are implicated in the mechanism of action of the pro-convulsive agent, 4-aminopyridine (4-AP). In the present study the effects of levetiracetam and other established and newer (vinpocetine) anti-epileptic drugs, as well as of the anti-depressant, sertraline on the increase in Ca2+ induced by 4-AP in hippocampal isolated nerve endings were investigated. Also the effects of some of the anti-seizure drugs on the selective increase in Ca2+ induced by high K+, or on the selective increase in Na+ induced by veratridine were tested. Sertraline and vinpocetine effectively inhibited the rise in Ca2+ induced by 4-AP, which was dependent on the out-in Na+ gradient and tetrodotoxin sensitive. Carbamazepine, phenytoin, lamotrigine and oxcarbazepine inhibited the rise in Ca2+ induced by 4-AP too, but at higher concentrations than sertraline and vinpocetine, whereas levetiracetam, valproic acid and topiramate did not. The three latter antiepileptic drugs also failed in modifying other responses mediated by the activation of brain presynaptic Na+ or Ca2+ channels, including Glu release. This indicates that levetiracetam, valproic acid and topiramate mechanisms of action are unrelated with a decrease in presynaptic Na+ or Ca2+ channels permeability. It is concluded that depolarized cerebral isolated nerve endings represent a useful tool to unmask potential antiepileptic drugs targeting presynaptic Na+ and/or Ca2+ channels in the brain; such as vinpocetine or the anti-depressant sertraline, which high effectiveness to control seizures in the animal in vivo has been demonstrated.

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Acknowledgments

The authors thank Araceli Guarneros for her excellent technical assistance. This study was financially supported by the “Programa de Apoyos para la Superación del Personal Académico (PASPA)”, UNAM.

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Authors and Affiliations

  1. Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, 04510, Mexico City, Mexico

    María Sitges & Luz María Chiu

  2. Department of Pharmacy Practice, School of Pharmacy, Husson University, One College Circle, Bangor, ME, 04401-2999, USA

    Ronald C. Reed

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  1. María Sitges
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Correspondence to María Sitges.

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All experiments were conducted in compliance with the ARRIVE guidelines. The authors declare that they have no conflicts of interest.

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Sitges, M., Chiu, L.M. & Reed, R.C. Effects of Levetiracetam, Carbamazepine, Phenytoin, Valproate, Lamotrigine, Oxcarbazepine, Topiramate, Vinpocetine and Sertraline on Presynaptic Hippocampal Na+ and Ca2+ Channels Permeability. Neurochem Res 41, 758–769 (2016). https://doi.org/10.1007/s11064-015-1749-0

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