N(6)-2-(4-aminophenyl)ethyl-adenosine enhances the anticonvulsive action of conventional antiepileptic drugs in the kindling model of epilepsy in rats.
APNEA [(N(6)-2-(4-aminophenyl)ethyl-adenosine; a non-selective adenosine A(3) receptor agonist; 2-4 mgkg(-1)] had no significant effect on seizure parameters (seizure severity, seizure duration and afterdischarge duration) in amygdala-kindled rats. Subsequently, APNEA was combined with antiepileptic drugs administered at doses ineffective in fully kindled rats. Co-administration of APNEA (0.5-2 mg kg(-1)) with carbamazepine (2.5-20 mg kg(-1)) resulted in the significant reduction of all studied seizure parameters. Moreover, 8-cyclopentyl-1,3-dimethylxanthine 8-CPX (a selective adenosine A(1) receptor antagonist; 5 mg kg(-1)) partially reduced the anticonvulsive activity of a combination of APNEA (2 mg kg(-1)) with carbamazepine (20 mg kg(-1)), but not that of carbamazepine (20 mgkg(-1))+APNEA (0.5 mg kg(-1)). When APNEA (2 mg kg(-1)) was combined with phenobarbital (20 mg kg(-1)), valproate (75 mg kg(-1)) or clonazepam (0.003 mg kg(-1)), seizure and afterdischarge durations were significantly shortened. 8-CPX (5 mg kg(-1)) totally reversed the APNEA (2 mg kg(-1))-induced enhancement of the anticonvulsive action of valproate. However, when the non-selective adenosine A(3) receptor agonist was administered together with diphenylhydantoin, no protection was observed in the kindling model of epilepsy. The interaction at the pharmacokinetic level can be excluded because APNEA did not interfere with the free plasma level of antiepileptics used in this study. It may be concluded that the interaction of APNEA with carbamazepine involves A(3) adenosine receptor-dependent events.
Borowicz
K K
KK
Department of Pharmacology and Toxicology, Lublin Medical University School, Jaczewskiego 8, 20-090, Lublin, Poland.
Kleinrok
Z
Z
Czuczwar
S J
SJ
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use; D000679:Amygdala; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000627:therapeutic use*; D001362:Avoidance Learning / Q000187:drug effects; D002220:Carbamazepine / Q000097:blood / Q000627:therapeutic use; D004195:Disease Models, Animal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004827:Epilepsy / Q000097:blood / Q000188:drug therapy*; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013806:Theophylline / Q000031:analogs & derivatives* / Q000494:pharmacology; D014635:Valproic Acid / Q000097:blood / Q000627:therapeutic use
D000927:Anticonvulsants; C086112:N(6)-2-(4-aminophenyl)ethyladenosine; D002220:Carbamazepine; C053907:8-cyclopentyl-1,3-dimethylxanthine; D014635:Valproic Acid; D013806:Theophylline; D000241:Adenosine