<abstract xmlns="http://www.w3.org/1999/xhtml"><sec id="j_joepi-2017-0006_s_001"><h3>Background</h3><p>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.</p></sec><sec id="j_joepi-2017-0006_s_002"><h3>Aim</h3><p>To evaluate effects of adenosine agonists on carbamazepine (CBZ) and valproate (VPA) in mouse model of generalized tonic-clonic convulsions.</p></sec><sec id="j_joepi-2017-0006_s_003"><h3>Methods</h3><p>The following adenosine receptor agonists were used: A<sub>1</sub> – cyclohexyladenosine, A<sub>2A</sub> – CGS 21 680, A<sub>3</sub> – N<sup>6</sup>-benzyl-NECA and A<sub>1</sub> (preferentially) and A<sub>2</sub> – 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 ED<sub>50</sub> 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 A<sub>1</sub> and A<sub>2</sub> 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.</p></sec><sec id="j_joepi-2017-0006_s_004"><h3>Results</h3><p>Adenosine receptor agonists (cycloheksyladenosine up to 4 mg/kg; CGS 21 680 – 8 mg/kg; N<sup>6</sup>-benzyl-NECA – 1 mg/kg; 2-chloroadenosine – 2 mg/kg) did not significantly affect the threshold for maximal electroconvulsions. Cycloheksyladenosine (1 mg/kg), N<sup>6</sup>-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 + N<sup>6</sup>-benzyl-NECA (1 mg/kg) was resistant to aminophylline (5 mg/kg). Pharmacokinetic interactions were evident in case of the combination of CBZ + N<sup>6</sup>-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 + N<sup>6</sup>-benzyl-NECA (1 mg/kg).</p></sec><sec id="j_joepi-2017-0006_s_005"><h3>Conclusion</h3><p>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.</p></sec></abstract>

BackgroundAdenosine 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.AimTo evaluate effects of adenosine agonists on carbamazepine (CBZ) and valproate (VPA) in mouse model of generalized tonic-clonic convulsions.MethodsThe 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.ResultsAdenosine 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).ConclusionThe 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.

Adenosine receptor agonists differentially affect the anticonvulsant action of carbamazepine and valproate against maximal electroshock test-induced seizures in mice

Journal of Epileptology

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

BackgroundAdenosine is regarded as an endogenous anticonvulsant and its agonists have been proved to affect the anticonvulsant activity of a number of...

Adenosine receptor agonists differentially affect the anticonvulsant action of carbamazepine and valproate against maximal electroshock test-induced seizures in mice

Published Online: Dec 15, 2018

Page range: 21 - 29

Received: Nov 30, 2017

Accepted: Dec 15, 2017

DOI: https://doi.org/10.21307/joepi-2017-0006

Keywords
adenosine receptor agonists, aminophylline, carbamazepine, valproate, electroconvulsions, mice

© 2017 Mirosław Jasiński et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Adenosine receptor agonists differentially affect the anticonvulsant action of carbamazepine and valproate against maximal electroshock test-induced seizures in mice

Published Online: Dec 15, 2018

Page range: 21 - 29

Received: Nov 30, 2017

Accepted: Dec 15, 2017

DOI: https://doi.org/10.21307/joepi-2017-0006

Keywordsadenosine receptor agonists, aminophylline, carbamazepine, valproate, electroconvulsions, mice

© 2017 Mirosław Jasiński et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Keywords
adenosine receptor agonists, aminophylline, carbamazepine, valproate, electroconvulsions, mice