Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 1.736
5-Year Impact Factor – 2.135
Index Copernicus  – 168.52
MEiN – 70 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
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Advances in Clinical and Experimental Medicine

2015, vol. 24, nr 4, July-August, p. 565–570

doi: 10.17219/acem/48265

Publication type: original article

Language: English

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Effect of Combined Treatment with AT1 Receptor Antagonists and Tiagabine on Seizures, Memory and Motor Coordination in Mice

Krzysztof Łukawski1,A,B,C,D,E,F, Agnieszka Janowska1,A,B,C,E,F, Stanisław J. Czuczwar1,2,A,C,E,F

1 Department of Physiopathology, Institute of Rural Health, Lublin, Poland

2 Department of Pathophysiology, Medical University of Lublin, Poland

Abstract

Background. Losartan and telmisartan, angiotensin AT1 receptor antagonists, are widely used antihypertensive drugs in patients. It is also known that arterial hypertension is often present in people with epilepsy, therefore, drug interactions between AT1 receptor antagonists and antiepileptic drugs can occur in clinical practice.
Objectives. The aim of the current study was to assess the effect of losartan and telmisartan on the anticonvulsant activity of tiagabine, a second-generation antiepileptic drug, in mice. Additionally, the effect of the combined treatment with AT1 receptor antagonists and TGB on long-term memory and motor coordination has been assessed in animals.
Material and Methods. The study was performed on male Swiss mice. Convulsions were examined in the maximal electroshock seizure threshold test. Long-term memory was measured in the passive-avoidance task and motor coordination was evaluated in the chimney test. AT1 receptor antagonists and TGB were administered intraperitoneally.
Results. Losartan (50 mg/kg) or telmisartan (30 mg/kg) did not influence the anticonvulsant activity of TGB applied at doses of 2, 4 and 6 mg/kg. However, both AT1 receptor antagonists in combinations with TGB (6 mg/kg) impaired motor coordination in the chimney test. The concomitant treatment of the drugs did not decrease retention in the passive avoidance task.
Conclusion. It is suggested that losartan and telmisartan should not affect the anticonvulsant action of TGB in people with epilepsy. Because the combined treatment with AT1 receptor antagonists and TGB led to neurotoxic effects in animals, caution is advised during concomitant use of these drugs in patients.

Key words

losartan, telmisartan, tiagabine, electroconvulsions, memory, locomotor activity.

References (33)

  1. Farsang C: Indications for and utilization of angiotensin receptor II blockers in patients at high cardiovascular risk. Vasc Health Risk Manag 2011, 7, 605–622.
  2. Gaitatzis A, Carroll K, Majeed A, Sander JW: The epidemiology of the comorbidity of epilepsy in the general population. Epilepsia 2004, 45, 1613–1622.
  3. Téllez-Zenteno JF, Matijevic S, Wiebe S: Somatic comorbidity of epilepsy in the general population in Canada. Epilepsia 2005, 46, 1955–1962.
  4. Wright JW, Harding JW: Brain renin-angiotensin – a new look at an old system. Prog Neurobiol 2011, 95, 49–67.
  5. Culman J, vonHeyer C, Piepenburg B, Rascher W, Unger T: Effects of systemic treatment with irbesartan and losartan on central responses to angiotensin II in conscious, normotensive rats. Eur J Pharmacol 1999, 367, 255–265.
  6. Gohlke P, Weiss S, Jansen A, Wienen W, Stangier J, Rascher W, Culman J, Unger T: AT1 receptor antagonist telmisartan administered peripherally inhibits central responses to angiotensin II in conscious rats. J Pharmacol Exp Ther 2001, 298, 62–70.
  7. Raghavendra V, Chopra K, Kulkarni SK: Involvement of cholinergic system in losartan-induced facilitation of spatial and short-term working memory. Neuropeptides 1998, 32, 417–421.
  8. Tchekalarova J, Georgiev V: Angiotensin peptides modulatory system: how is it implicated in the control of seizure susceptibility? Life Sci 2005, 76, 955–970.
  9. Pereira MG, Becari C, Oliveira JA, Salgado MC, Garcia-Cairasco N, Costa-Neto CM: Inhibition of the reninangiotensin system prevents seizures in a rat model of epilepsy. Clin Sci (Lond) 2010, 119, 477–482.
  10. Georgiev VP, Lazarova MB, Kambourova TS: Effects of non-peptide angiotensin II-receptor antagonists on pentylenetetrazol kindling in mice. Neuropeptides 1996, 30, 401–404.
  11. Łukawski K, Janowska A, Jakubus T, Tochman-Gawda A, Czuczwar SJ: Angiotensin AT1 receptor antagonists enhance the anticonvulsant action of valproate in the mouse model of maximal electroshock. Eur J Pharmacol 2010, 640, 172–177.
  12. Łukawski K, Janowska A, Jakubus T, Raszewski G, Czuczwar SJ: Combined treatment with gabapentin and drugs affecting the renin-angiotensin system against electroconvulsions in mice. Eur J Pharmacol 2013, 706, 92–97.
  13. Łukawski K, Janowska A, Jakubus T, Czuczwar SJ: Interactions between angiotensin AT1 receptor antagonists and second-generation antiepileptic drugs in the test of maximal electroshock. Fundam Clin Pharmacol 2013, 28(3). DOI: 10.1111/fcp.12023.
  14. Czuczwar SJ, Patsalos PN: The new generation of GABA enhancers. CNS Drugs 2001, 15, 339–350.
  15. Löscher W, Fassbender CP, Nolting B: The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models. Epilepsy Res 1991, 8, 79–94.
  16. Venault P, Chapouthier G, Prado de Carvalho L, Simiand J, Morre M, Dodd RH, Rossier J: Benzodiazepine impairs and β-carboline enhances performance in learning and memory tasks. Nature 1986, 321, 864–866.
  17. Boissier JR, Tardy J, Diverres JC: Une nouvelle methode simple pour explorer l’action ‘tranquilisante’: le test de la cheminee. Med Exp (Basel) 1960, 3, 81–84.
  18. Łuszczki JJ, Czuczwar SJ: Isobolographic profile of interactions between tiagabine and gabapentin: a preclinical study. Naunyn Schmiedebergs Arch Pharmacol 2004, 369, 434−446.
  19. Litchfield JT, Wilcoxon F: A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther 1949, 96, 99–113.
  20. Łuszczki JJ, Borowicz KK, Swiąder M, Czuczwar SJ: Interactions between oxcarbazepine and conventional antiepileptic drugs in the maximal electroshock test in mice: an isobolographic analysis. Epilepsia 2003, 44, 489–499.
  21. Czapiński P, Blaszczyk B, Czuczwar SJ: Mechanisms of action of antiepileptic drugs. Curr Top Med Chem 2005, 5, 3–14.
  22. Leach JP, Sills GJ, Majid A, Butler E, Carswell A, Thompson GG, Brodie MJ: Effects of tiagabine and vigabatrin on GABA uptake into primary cultures of rat cortical astrocytes. Seizure 1996, 5, 229–234.
  23. Dalby NO, Nielsen EB: Comparison of the preclinical anticonvulsant profiles of tiagabine, lamotrigine, gabapentin and vigabatrin. Epilepsy Res 1997, 28, 63–72.
  24. Łuszczki JJ, Świąder M, Parada-Turska J, Czuczwar SJ: Tiagabine synergistically interacts with gabapentin in the electroconvulsive threshold test in mice. Neuropsychopharmacology 2003, 28, 1817–1830.
  25. Chrościńska-Krawczyk M, Ratnaraj N, Patsalos PN, Czuczwar SJ: Effect of caffeine on the anticonvulsant effects of oxcarbazepine, lamotrigine and tiagabine in a mouse model of generalized tonic-clonic seizures. Pharmacol Rep 2009, 61, 819–826.
  26. Łukawski K, Jakubus T, Czuczwar SJ: Lack of effect of ACE inhibitors on the anticonvulsant activity of tiagabine in the maximal electroshock seizure threshold test in mice. J Epileptol 2012, 20, 17–22.
  27. Chen QH, Toney GM: Responses to GABA-A receptor blockade in the hypothalamic PVN are attenuated by local AT1 receptor antagonism. Am J Physiol Regul Integr Comp Physiol 2003, 285, 1231–1239.
  28. Li DP, Pan HL: Angiotensin II attenuates synaptic GABA release and excites paraventricular-rostral ventrolateral medulla output neurons. J Pharmacol Exp Ther 2005, 313, 1035–1045.
  29. Unger T, Bles F, Ganten D, Lang RE, Rettig R, Schwab NA: Gabaergic stimulation inhibits central actions of angiotensin II: pressor responses, drinking and release of vasopressin. Eur J Pharmacol 1983, 90, 1–9.
  30. Hagiwara Y, Kubo T: Intracerebroventricular injection of losartan inhibits angiotensin II-sensitive neurons via GABA inputs in the anterior hypothalamic area of rats. Neurosci Lett 2007, 416, 150–154.
  31. Thach WT, Goodkin HP, Keating JG: The cerebellum and the adaptive coordination of movement. Annu Rev Neurosci 1992, 15, 403–442.
  32. Hori K, Hoshino M: GABAergic neuron specification in the spinal cord, the cerebellum, and the cochlear nucleus. Neural Plast 2012 Jun 28. DOI: 10.1155/2012/921732.
  33. Milić M, Divljaković J, Rallapalli S, van Linn ML, Timić T, Cook JM, Savić MM: The role of á1 and á5 subunitcontaining GABAA receptors in motor impairment induced by benzodiazepines in rats. Behav Pharmacol 2012, 23, 191–197.