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This article is part of the supplement: 18th Scientific Symposium of the Austrian Pharmacological Society (APHAR)

Open Access Meeting abstract

Antiepileptic activity and subtype-selective action of flupirtine at GABAA receptors

Mirnes Bajrić, Felicia Klinger, Ulla Schandl, Helmut Kubista and Stefan Boehm*

Author Affiliations

Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria

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BMC Pharmacology and Toxicology 2012, 13(Suppl 1):A90  doi:10.1186/2050-6511-13-S1-A90

The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/2050-6511/13/S1/A90


Published:17 September 2012

© 2012 Bajrić et al; licensee BioMed Central Ltd.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background

Flupirtine is used as analgesic drug with muscle-relaxant properties. In addition, it has been suggested to possess antiepileptic properties. Recently, flupirtine has been revealed to simultaneously act at KV7 channels and GABAA receptors. Here, antiepileptic activity and underlying mechanisms of action of flupirtine were investigated.

Methods

We used the patch clamp technique and primary cultures of hippocampal neurons or transfected tsA cells to investigate effects of flupirtine.

Results

In hippocampal neurons, flupirtine reduced seizure-like activity with no effect at 1 to 3 µM, and maximal effects at 10 to 30 µM; it enhanced currents through KV7 channels with EC50 values at 6 µM. Flupirtine (30 µM) modulated GABA-induced currents in hippocampal neurons by reducing EC50 values for GABA threefold and maximal current amplitudes by 15%. Hence, flupirtine acted as an uncompetitive antagonist. Flupirtine did not alter rise time, decay time, or amplitudes of miniature inhibitory postsynaptic currents (mIPSCs), but enhanced the bicuculline-sensitive tonic current. When phasic GABAergic inhibition was blocked by penicillin G (5 mM), flupirtine enhanced maximal amplitudes of GABA-evoked currents by 43%, but hardly affected EC50 values. As these results suggested that flupirtine was able to differentiate between different GABAA receptor subtypes, its effects on recombinant GABAA receptors were investigated in tsA cells. With α1β2γ2 receptors, flupirtine reduced EC50 values for GABA threefold and maximal current amplitudes by 25%; with α1β2 receptors, it reduced EC50 values for GABA twofold, but reduced maximal current amplitudes by 35%.

Conclusions

These results indicate that flupirtine (i) exerts antiepileptic activity, (ii) modulates tonic, but not phasic, GABAergic inhibition and blocks KV7 channels in hippocampal neurons, and (iii) affects GABAA receptors in a subunit-dependent manner.

Acknowledgements

This study is supported by the Austrian Science Fund (P23658).