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Cytisine inhibits the protective activity of various classical and novel antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice

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Abstract

Background

Cytisine (CYT) is a partial agonist of brain α4β2 nicotinic acetylcholine receptors widely used in Central/Eastern Europe for smoking cessation.

Objectives

This study evaluated the effect of CYT on the ability of classical and novel antiepileptic drugs to prevent seizures evoked by the 6-Hz test, a model of psychomotor seizures in mice thought as a model of drug-resistant seizures.

Results

CYT administered intraperitoneally (i.p.) in a dose of 2 mg kg−1 significantly inhibited the anticonvulsant activity of lacosamide, levetiracetam, and pregabalin, increasing their median effective doses 50 (ED50) values from 6.88 to 10.52 mg kg−1 (P < 0.05) for lacosamide, from 22.08 to 38.26 mg kg−1 (P < 0.05) for levetiracetam, and from 40.48 to 64.61 mg kg−1 (P < 0.01) for pregabalin, respectively. There were no significant changes in total brain concentrations of lacosamide, levetiracetam, and pregabalin following CYT i.p. administration. CYT administered in a dose of 2 mg kg−1 failed to change the protective action of clobazam, clonazepam, phenobarbital, tiagabine, and valproate in the 6-Hz test. Neither CYT (2 mg kg−1) alone nor its combination with the anticonvulsant drugs (at their ED50 values from the 6-Hz test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; and grip strength and passive avoidance tests, respectively.

Conclusion

CYT-evoked alterations in the protection provided by some antiepileptic drugs against seizures can be of serious concern for epileptic smokers, who might demonstrate therapeutic failure to lacosamide, levetiracetam, and pregabalin, resulting in possible breakthrough seizure attacks.

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Acknowledgments

This study was supported by a research grant from the University of Rzeszów (Rzeszów, Poland) (DS/2014, DS/2015). The authors express their thanks to Dr. G. Raszewski (Institute of Rural Health, Lublin, Poland) for the skillful determination of the brain concentrations of antiepileptic drugs.

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Authors and Affiliations

  1. Department of Pharmacology, University of Rzeszów, Al. Rejtana 16c, 35-959, Rzeszów, Poland

    Piotr Tutka

  2. Centre for Innovative Research in Medical and Natural Sciences, University of Rzeszów, Pigonia 1, 35-959, Rzeszów, Poland

    Piotr Tutka

  3. Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8b, 20-090, Lublin, Poland

    Maria W. Kondrat-Wróbel, Katarzyna Zaluska & Jarogniew J. Łuszczki

  4. Department of Neurology, School of Medicine, University of California–Davis, Sacramento, CA, USA

    Dorota Żółkowska

  5. Centre of Public Health and Health Promotion, Institute of Rural Health, Jaczewskiego 2, 20-950, Lublin, Poland

    Magdalena Florek-Łuszczki

  6. Isobolographic Analysis Laboratory, Institute of Rural Health, Jaczewskiego 2, 20-950, Lublin, Poland

    Jarogniew J. Łuszczki

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  1. Piotr Tutka
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  2. Maria W. Kondrat-Wróbel
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  3. Katarzyna Zaluska
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  4. Dorota Żółkowska
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  5. Magdalena Florek-Łuszczki
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  6. Jarogniew J. Łuszczki
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Corresponding author

Correspondence to Piotr Tutka.

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The experimental procedures listed were approved by the Second Local Ethics Committee at the University of Life Sciences in Lublin (license nos. 88/2012 and 61/2014) and conformed to the Guide for the Care and Use of Laboratory Animals.

Conflict of interest

Prof. P Tutka has undertaken paid consultancy for Aflofarm, a manufacturer of CYT. Prof. JJ Luszczki has been involved in the design and development of new antiepileptics and CNS drugs. Additionally, within the last 5 years, he has received an unrestricted research grant from GlaxoSmithKline (Brentford, UK). The remaining authors have no conflicts of interest to disclose.

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Tutka, P., Kondrat-Wróbel, M.W., Zaluska, K. et al. Cytisine inhibits the protective activity of various classical and novel antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice. Psychopharmacology 234, 281–291 (2017). https://doi.org/10.1007/s00213-016-4461-0

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