Comparison of effects and electrophysiological mechanisms of action of valproic acid and levetyracetam in an experimental model of focal epilepsy

Abstract

Introduction. Despite rapid development of the antiepileptic pharmaceuticals market, about 2/3 of patients suffering from epilepsy do not receive adequate treatment, which is partly due to the variety of mechanisms for the development of epileptic seizures

Objective. А comparative study of the electrophysiological mechanisms of action and effects of valproic acid (Depakin Chrono) and levetiracetam (Levetinol) under experimental focal epilepsy and status epilepticus (SE) in rats.

Materials and methods. Focal chronic epilepsy was caused by the application of cobalt to the sensorimotor cortex. On the 7th–8th day, SE was modeled by the injection of homocysteine, which provoked the development of secondary generalized tonic-clonic seizures.

Results. Levetiracetam had a suppressing effect on the paroxysmal activity of the rat brain only under conditions of a stable SE on the 5th–6th day after the application of cobalt. Its most prominant effect was seen in the hippocampus and was characterized by a significant decrease in epileptic activity (EpiA) in this structure and in the maintenance of a regular rhythm. Valproic acid significantly suppressed EpiA in the ipsilateral cortex, hippocampus and hypothalamus at a stable stage of EpiS development, with the most pronounced effect on the primary cortical focus and hypothalamus. In the model of SE caused by the injection of homocysteine, levetiracetam was ineffective, whereas valproic acid decreased the severity of paroxysmal activity in all the studied structures, especially in the cortex (ipsi- and contralateral, 33 times) and hypothalamus (28 times), which was accompanied by suppression of generalized motor manifestations and reduced number of animal deaths.

Conclusion. In the model of focal cobalt-induced epilepsy, the hippocampus is the leading structure and the target of the levetiracetam action, while the effect of valroic acid is executed through the inhibitory effect on the cortical foci of EpiA and the hypothalamus, which may be main feature in its ability to suppress the SE.

About the authors

Svetlana A. Litvinova

Research Zakusov Institute of Pharmacology, Moscow

Author for correspondence.
Email: platonova@neurology.ru
Russian Federation

Georgii G. Avakyan

Pirogov Russian National Research Medical University, Moscow

Email: platonova@neurology.ru
Russian Federation

Tatyana А. Voronina

Research Zakusov Institute of Pharmacology, Moscow

Email: platonova@neurology.ru
Russian Federation

Igor O. Gaidukov

Research Zakusov Institute of Pharmacology, Moscow

Email: platonova@neurology.ru
Russian Federation

Lyubov N. Nerobkova

Research Zakusov Institute of Pharmacology, Moscow

Email: platonova@neurology.ru
Russian Federation

Inga S. Kutepova

Research Zakusov Institute of Pharmacology, Moscow

Email: platonova@neurology.ru
Russian Federation

Gagik N. Avakyan

Pirogov Russian National Research Medical University, Moscow

Email: platonova@neurology.ru
Russian Federation

References

  1. Belousov Yu.B., Belousov D.Yu., Chikina E.S. [Research of medical and social problems of epilepsy in Russia]. Kachestvennaya klinicheskaya praktika 2004; 4 (Special Issue): 89. (In Russ.)
  2. WHO. Global burden of epilepsy and the need for coordinated action at the country level to address its health. Social and public knowledge implications. 2 February 2015.
  3. Karlov V.A. Epilepsiya u detei i vzroslykh zhenshchin i muzhchin [Epilepsy in children and adult women and men]. Moscow; 2010; 720 p. (In Russ.)
  4. Vreugdenhil M., Wadman W.J. Modulation of sodium currents in rat CA1 neurons by carbamazepine and valproate after kindling epileptogenesis. Epilepsia 1999; 40: 1512–1522. PMID: 10565577.
  5. Ueda Y., Willmore L.J. Molecular regulation of glutamate and GABA transporter proteins by valproic acid in rat hippocampus during epileptogenesis. Exp Brain Res 2000; 133: 334–339. PMID: 10958523
  6. Wakita M., Kotani N., Kogure K., Akaike N. Inhibition of excitatory synaptic transmission in hippocampal neurons by levetiracetam involves Zn2+-dependent GABA type A receptor-mediated presynaptic modulation. J Pharmacol Exp Ther 2014; 348: 246–259. PMID: 24259680.
  7. Gillard M., Fuks B., Michel P. et al. Binding characteristics of [3H]ucb 30889 to levetiracetam binding sites in rat brain. Eur J Pharmacol. 2003; 478:1– 910.1016. PMID: 14555178.
  8. Gillard M., Chatelain P., Fuks B. Binding characteristics of levetiracetam to synaptic vesicle protein 2A (SV2A) in human brain and in CHO cells expressing the human recombinant protein. Eur J Pharmacol. 2006; 536: 102–810. doi: 10.1016/j.ejphar.2006.02.022. PMID: 16556440.
  9. Lynch B.A., Lambeng N., Nocka K., Kensel-Hammes P. et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA. 2004; 101: 9861–9866. doi: 10.1073/pnas.0308208101. PMID: 15210974.
  10. Angehagen M., Margineanu D.G., Ben-Menachem E. et al. Levetiracetam reduces caffeine-induced Ca2+ transients and epileptiform potentials in hippocampal neurons. Neuroreport. 2003; 14: 471–475 doi: 10.1097/01. wnr.0000059774.23521.b7. PMID: 12634506.
  11. Carunchio I., Pieri M., Ciotti M.T. et al. Modulation of AMPA receptors in cultured cortical neurons induced by the antiepileptic drug levetiracetam. Epilepsia. 2007; 48: 654–662. doi: 10.1111/j.1528-1167.2006.00973.x. PMID: 17284293.
  12. Cataldi M., Lariccia V., Secondo A. et al. The antiepileptic drug levetiracetam decreases the inositol 1,4,5-trisphosphate-dependent [Ca2+]I increase inducedby ATP and bradykinin in PC12 cells. J Pharmacol Exp Ther. 2005; 313: 720–730. doi: 10.1124/jpet.104.079327. PMID: 15644427.
  13. Klitgaard H. Levetiracetam: the preclinical profile of a new class of antiepileptic drugs? Epilepsia 2001; 42: 13–18. PMID: 11564119.
  14. Palma E., Ragozzino D., Di Angelantonio S. et al. The antiepileptic drug levetiracetam stabilizes the human epileptic GABAA receptors upon repetitive activation. Epilepsia. 2007; 48: 1842–1849. doi: 10.1111/j.1528-1167.2007.01131.x. PMID: 17521347.
  15. Rigo J.M., Hans G., Nguyen L. et al. The anti-epileptic drug levetiracetam reverses the inhibition by negative allosteric modulators of neuronal GABA- and glycine-gated currents. Br J Pharmacol. 2002; 136: 659–672. doi: 10.1038/sj.bjp.0704766. PMID: 12086975.
  16. Wakita M., Kotani N., Kogure K., Akaike N. Inhibition of excitatory synaptic transmission in hippocampal neurons by levetiracetam involves Zn2+-dependent GABA type A receptor-mediated presynaptic modulation. J Pharmacol Exp Ther. 2014; 348: 246–259. doi: 10.1124/jpet.113.208751. PMID: 24259680.
  17. Margineanu D.G., Wulfert E. ucb L059, a novel anticonvulsant, reduces bicuculline-induced hyperexcitability in rat hippocampal CA3 in vivo. Eur J Pharmacol1995; 286: 321–325. PMID: 8608796.
  18. Birnstiel S., Wulfert E., Beck S.G. Levetiracetam (ucb LO59) affects in vitro models of epilepsy in CA3 pyramidal neurons without altering normal synaptictransmission. Naunyn Schmiedebergs Arch Pharmacol 1997; 356: 611–618. PMID: 9402041.
  19. Avakyan G.N., Nerobkova L.N., Voronina Т.А. et al. [Effect of carbamazepine on structurally functional connections in the development of the epileptic system]. Eksp Klin Farmakol 2002; 2: 7–10. (In Russ.)
  20. Bregman F., Le Saux S., Trottier P. et al. Chronic cobalt-induced epilepsy: noradrenaline ionophoresis and adrenoceptor binding studies in the rat cerebralcortex. J. Neural Transmission. 1985; 63: 109–118.
  21. Voronina T.A., Stoiko M.I., Nerobkova L.N. et al. [Investigation of the effectof fenitoin on the development of homocysteine induced convulsions and epileptic status in rats with cobalt-induced epilepsy]. Eksp Klin Farmakol 2002; 65: 15–8. (In Russ.)
  22. Walton N.Y., Treiman D.M. Efficacy of ACC-9653 (a phenytoin prodrug) in experimental status epilepticus in the rat. Epilepsy Res 1990; 5: 165–168. PMID: 2328717.
  23. Walton N.Y., Treiman D.M. Valproic acid treatment of experimental status epilepticus. Epilepsy Res 1992; 12: 199–205. PMID: 1396545.
  24. Walton N.Y., Jaing Q., Hyun B., Treiman D.M. Lamotrigine vs. phenytoin for treatment of status epilepticus: comparison in an experimental model. Epilepsy Res 1996; 24: 19–28. PMID: 8800632.
  25. Voronina T.A., Nerobkova L.N. Metodicheskiye ukazaniya po izucheniyu protivosudorozhnoy aktivnosti farmakologicheskikh veshchestv. Rukovodstvo po provedeniyu doklinicheskikh issledovaniy lekarstvennykh sredstv [Methodical instructions on the study of anticonvulsant activity of pharmacological substances. A guide to preclinical drug research]. Moscow; 2012: 235–250. (In Russ.)
  26. Buresh J., Petran M., Zahar D. Elektrofiziologicheskiye metody issledovaniya v biologii [Electrophysiological methods of research in biology]. Мoscow; 1964: 551. (In Russ.)
  27. Walton N.Y., Treiman D.M. Experimental secondarily generalized convulsive status epilepticus induced by D, L-homocysteine thiolactone. Epilepsy Res 1988; 2: 79–86. PMID: 3197690.
  28. Avakyan G.G. [Clinico-neurophysiological study of combinations of new forms of anticonvulsant and antioxidant in patients with epilepsy with secondary generalized attacks: Author’s Abstract of PhD Thesis]. Мoscow; 2011. (In Russ.)

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Copyright (c) 2018 Litvinova S.A., Avakyan G.G., Voronina T.А., Gaidukov I.O., Nerobkova L.N., Kutepova I.S., Avakyan G.N.

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