N6-cyclohexyladenosine and 3-(2-carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid enhance the effect of antiepileptic drugs against induced seizures in mice.
OBJECTIVE
The influence of N(6)-Cyclohexyladenosine (CHA), an adenosine A(1) agonist and 3-(2-Carboxypiperazine-4-yl)-1-propenyl-1-phosphonic acid (CPPene), a selective N-methyl-D-aspartate (NMDA) antagonist upon the anticonvulsant activity of diazepam (DA), sodium valproate (VP), diphenylhydantoin (DPH), phenobarbital (PB) and carbamazepine (CAZ) was investigated in mice. All agents were administered intraperitoneally.


METHODS
Convulsive seizures were induced by the use of electro shocks and pentylenetetrazole (PTZ).


RESULTS
CHA (2 mg/kg, i.p.) and CPPene (2.5 mg/kg, i.p.) were found to enhance the anticonvulsant activity of the tested antiepileptic drugs against both electro convulsions and PTZ-induced convulsions. Both CHA and CPPene significantly decreased the ED50 values of these drugs against both electro convulsions and PTZ-induced convulsions, and increased the convulsive threshold. CHA (2 mg/kg, i.p.) and CPPene (2.5 mg/kg, i.p.) did not affect the plasma level of any of the tested antiepileptic drugs, indicating no pharmacokinetic interactions at the systemic administration. CHA (2 mg/kg, i.p.) or CPPene (2.5 mg/kg, i.p.), alone or in combination with the tested antiepileptic drugs produced no significant changes in their effects on the heart rate, blood pressure, body temperature, gross behavior or on the locomotor activity of experimental animals. Combinations of the antiepileptic drugs with CHA (2 mg/kg, i.p.) or CPPene (2.5 mg/kg, i.p.) were also devoid of significant effects on the motor performance and long-term memory in mice demonstrated by the Chimney test and passive avoidance task. CHA (5 mg/kg, i.p.) alone or in combination with the tested antiepileptic drugs produced inhibition of locomotor activity and motor coordination, sedation and hypothermia as well as impairing of long-term memory.


CONCLUSIONS
Adenosine A1 agonists and NMDA antagonists enhance the efficacy of common antiepileptic drugs, indicating the involvement of adenosine and NMDA receptors in the convulsive pathway. The potential therapeutic benefits of such interactions may be taken into consideration and merit further investigations in animals and humans.
Assi
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Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut, Egypt. assi@wpo.nccu.edu
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000627:therapeutic use*; D001362:Avoidance Learning / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D003975:Diazepam / Q000097:blood / Q000627:therapeutic use; D004195:Disease Models, Animal; D004357:Drug Synergism; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole; D010634:Phenobarbital / Q000097:blood / Q000627:therapeutic use; D010879:Piperazines / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D012153:Retention, Psychology / Q000187:drug effects; D012640:Seizures / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; C065286:SDZ EAA 494; C027513:N(6)-cyclohexyladenosine; D000241:Adenosine; D003975:Diazepam; D010433:Pentylenetetrazole; D010634:Phenobarbital