Background. Adenosine is regarded as an endogenous anticonvulsant and its agonists have been proved to affect the anticonvulsant activity of a number of antiepileptic drugs (AEDs) in animal models of seizures.
Aim. To evaluate effects of adenosine agonists on carbamazepine (CBZ) and valproate (VPA) in mouse model of generalized tonic-clonic convulsions.
Methods. The following adenosine receptor agonists were used: A1 – cyclohexyladenosine, A2A – CGS 21 680, A3 – N6-benzyl-NECA and A1 (preferentially) and A2 – 2-chloroadenosine. Their possible anticonvulsant effects were studied in a threshold electroconvulsive test for maximal electroconvulsions. The protective activity of AEDs alone or in combinations with adenosine agonists was evaluated in the form of their respective ED50 values necessary to protect 50% of mice against tonic extension of the hind limbs, following maximal electroshock, delivered through ear electrodes. The specificity of interactions between AEDs and adenosine agonists was challenged with an adenosine receptor A1 and A2 antagonist, aminophylline (5 mg/kg). The effects of AEDs alone or with adenosine agonists were tested for the occurrence of adverse effects (AE) (impairment of motor coordination) in a chimney test. All combinations with an enhancement the protective activity of CBZ or VPA were verified with the free plasma or brain concentration of these AED.
Results. Adenosine receptor agonists (cycloheksyladenosine up to 4 mg/kg; CGS 21 680 – 8 mg/kg; N6-benzyl-NECA – 1 mg/kg; 2-chloroadenosine – 2 mg/kg) did not significantly affect the threshold for maximal electroconvulsions. Cycloheksyladenosine (1 mg/kg), N6-benzyl-NECA (0.5 and 1 mg/kg) and 2-chloroadenosine (1 mg/kg) potentiated the anticonvulsant activity of CBZ. Valproate’s protective action was enhanced by one adenosine agonist – cycloheksyladenosine (1 mg/kg). Only the combination of CBZ + N6-benzyl-NECA (1 mg/kg) was resistant to aminophylline (5 mg/kg). Pharmacokinetic interactions were evident in case of the combination of CBZ + N6-benzyl-NECA (1 mg/kg) and resulted in an increased free plasma concentration of this CBZ. Interestingly, total brain concentration of CBZ confirmed the pharmacokinetic interaction as regards CBZ + N6-benzyl-NECA (1 mg/kg).
Conclusion. The best profile was shown by the combination of CBZ + 2-chloroadenosine which involved no AE or a pharmacokinetic interaction. The remaining positive combinations in terms of anticonvulsant activity were associated with general profound AE and pharmacokinetic interactions in some of them.
Abbracchio M.P., Brambilla R., Ceruti S., Kim H.O., von Lubitz D.K., Jacobson K.A. et al.:G protein-dependent activation of phospholipase C by adenosine A3 receptors in rat brain. Mol. Pharmacol., 1995; 48: 1038–1045.
Assi A.A.:N6-cyclohexyladenosine and 3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid enhance the effect of antiepileptic drugs against induced seizures in mice. J. Pharm. Sci., 2001, 4: 42–51.
Booker S.A., Pires N., Cobb S., Soares-da-Silva P., Vida I.:Carbamazepine and oxcarbazepine, but not eslicarbazepine, enhance excitatory synaptic transmission onto hippocampal CA1 pyramidal cells through an antagonist action at adenosine A1 receptors. Neuropharmacology, 2015, 93: 103–115.
Borowicz K.K., Kamiński R., Gasior M., Kleinrok Z., Czuczwar S.J.:Influence of melatonin upon the protective action of conventional anti-epileptic drugs against maximal electroshock in mice. Eur. Neuropsychopharmacol., 1999, 9: 185–190.
Borowicz K.K., Kleinrok Z., Czuczwar S.J.:N6-2-(4-aminophenyl) ethyl-adenosine enhances the anticonvulsive activity of antiepileptic drugs. Eur. J. Pharmacol., 1997, 327: 125–133.
Borowicz K.K., Kleinrok Z., Czuczwar S.J.:N(6)-2-(4-aminophenyl) ethyl-adenosine enhances the anticonvulsive action of conventional antiepileptic drugs in the kindling model of epilepsy in rats. Eur. Neuropsychopharmacol., 2000, 10: 237–243.
Borowicz K.K., Łuszczki J., Czuczwar S.J:. 2-Chloroadenosine, a preferential agonist of adenosine A1 receptors, enhances the anticonvulsant activity of carbamazepine and clonazepam in mice. Eur. Neuropsychopharmacol., 2002, 12: 173–179.
Bynoe M.S., Viret C., Yan A., Kim D.G.:Adenosine receptor signaling: a key to opening the blood-brain door. Fluids Barriers CNS, 2015, 12: 20. doi: 10.1186/s12987-015-0017-7.
Cieślak M., Wojtczak A,. Komoszyński M.:Role of the purinergic signaling in epilepsy. Pharmacol Rep., 2017, 69: 130–138.
Czapiński P., Błaszczyk B., Czuczwar S.J.:Mechanisms of action of antiepileptic drugs. Curr. Top. Med. Chem., 2005, 5: 3–14.
Daly J.W., Butts-Lamb P., Padgett W.:Subclasses of adenosine receptors in the central nervous system: Interactions with caffeine and related methylxanthines. Cell. Mol. Nerobiol., 1983, 3: 69–80.
Jasiński M., Chrościńska-Krawczyk M., Kaczmarczyk K., Czuczwar S.J.:Various adenosine receptor agonists differentially affect the anticonvulsant action of phenobarbital and phenytoin against maximal electroshock-induced seizures in mice. Epileptologia, 2011, 19: 5–15.
Litchfield, J.T., Wilcoxon, F.:A simplified method of evaluating dose–effect experiments. J. Pharmacol. Exp. Ther., 1949, 96: 99–113.
Löscher W., Schmidt D.:Which animal models should be used in the search for new antiepileptic drugs? A proposal based on the experimental and clinical considerations. Epilepsy Res., 1988, 2: 145–181.
Löscher W.:New visions in the pharmacology of anticonvulsion. Eur. J. Pharmacol., 1998, 342: 1–13.
Łuszczki J.J., Czuczwar S.J.:How significant is the difference between drug doses influencing the threshold for electroconvulsions? Pharmacol. Rep., 2005, 57: 782–786.
Łuszczki J.J., Kozicka M., Świąder M.J., Czuczwar S.J.:2-Chloro-N6-cyclopentyladenosine enhances the anticonvulsant action of carbamazepine in the mouse maximal electroshock-induced seizure model. Pharmacol. Rep., 2005, 57: 787–894.
Macdonald R.L.:Carbamazepine. Mechanisms of action. In: R.H. Levy, R.H. Mattson, B.S. Meldrum, E. Perucca (eds.), Antiepileptic Drugs, 5th edn. Lippincott Williams & Wilkins, Philadelphia, 2002, 227–235.
Malhotra J., Gupta Y.K.:Effect of sdenosine receptor modulation on pentylenetetrazole-induced seizures in rats. Br. J. Pharmacol., 1997, 120: 282–288.
Marangos P.J., Post R.M., Patel J., Zander K., Parma A., Weiss S.:Specific and potent interactions of carbamazepine with brain adenosine receptors. Eur. J. Pharmacol., 1983, 93: 175–182.
Miziak B., Chrościńska-Krawczyk M., Błaszczyk B., Radzik I., Czuczwar S.J.:Novel approaches to anticonvulsant drug discovery. Expert Opin. Drug Discov., 2013, 8: 1415–1427.
Ralevic V., Burnstock G.:Receptors for purines and pyrimidines. Pharmacol. Rev., 1998, 50: 415–492.
Schwartzkroin P.A.:Basic Mechanism of epileptogenesis. In: E. Wyllie (ed.), The Treatment of epilepsy: Principles and practice. Lea & Febiger, Philadelphia, 1993, 83–99.
Sebastião A.M., Ribeiro J.A.:Adenosine A2 receptor-mediated excitatory actions on the nervous system. Prog. Neurobiol., 1996, 48: 167–189.
Shorvon S.D.:The epidemiology and treatment of chronic and refractory epilepsy. Epilepsia, 1996, 37 (Suppl. 2): S1–S3.
Skerritt J.H., Davies L.P., Johnston G.A.:Interactions of the anticonvulsant carbamazepine with adenosine receptors. 1. Neurochemical studies. Epilepsia, 1983, 24: 634–642.
Sun Z., Zhong X.L., Zong Y., Wu Z.C., Zhang Q., Yu J.T. et al.:Activation of adenosine receptor potentiates the anticonvulsant effect of phenytoin against amygdala kindled seizures. CNS Neurol. Disord. Drug Targets, 2015, 14: 378–385.
Świąder M.J., Kotowski J., Łuszczki J.J.:Modulation of adenosinergic system and its application for the treatment of epilepsy. Pharmacol. Rep., 2014, 66: 335–342.
Van Calker D., Muller M., Hamprecht B.:Adenosine inhibits the accumulation of cyclic AMP in cultured brain cells. Nature, 1978, 276: 839–841.
Van Calker D., Steber R., Klotz K.N., Greil W.:Carbamazepine distinguishes between adenosine receptors that mediate different second messenger responses. Eur. J. Pharmacol., 1991, 206, 285–290.
Young D., Dragunow M.:Status epilepticus may be caused by loss of adenosine anticonvulsant mechanisms. Neuroscience, 1994, 58: 245–261.
Younus I., Reddy D.S.:A resurging boom in new drugs for epilepsy and brain disorders. Expert Rev. Clin. Pharmacol., 2017 – in press. doi: 10.1080/17512433.2018.1386553.
Zhang G., Franklin P.H., Murray T.F.:Manipulation of endogenous adenosine in the rat prepiriform cortex modulates seizure susceptibility. J. Pharmacol. Exp. Ther., 1993, 264: 1415–1424.
Zhou Q.Y., Li C., Olah M.E., Johnson R.A., Stiles G.L., Civelli O.:Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. Proc. Natl. Acad. Sci. USA, 1992, 89: 7432–7436.