Adenosinergic mechanisms in anticonvulsant action of diazepam and sodium valproate

The effects of adenosine receptor agonists and antagonists were studied in pentylenetetrazole (PTZ)-induced seizures in rats. Animals were pretreated with the non-specific adenosine receptor antagonist, theophylline (50 and 100 mg/kg, i.p.), or the specific A(1) adenosine receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), in a dose of 1 mg/kg, i.p., followed by 100% anticonvulsant doses of diazepam (4 mg/kg)/sodium valproate (300 mg/kg, i.p.). Subsequently, they were challenged with convulsant doses of PTZ i.e. 60 mg/kg, i.p. It was seen that while DPCPX could not reverse the protection of both the antiepileptic drugs, theophylline significantly reversed this protection, as assessed by percent incidence of seizures and change in latency parameters. In another set of experiments, the rats were pretreated with a combination of subanticonvulsant doses of adenosine (500 mg/kg) or specific adenosine A(1) receptor agonist, cyclopentyladenosine (CPA) and diazepam (0.5 and 1 mg/kg)/sodium valproate (150 mg/kg), prior to PTZ challenge. We observed a decrease in incidence and increase in latency of seizures following either combination. The protection observed was independent of the hypothermic and hypotensive effects of adenosine and CPA. These results indicate that though A(1) agonist enhances the protection of diazepam and sodium valproate, a direct involvement of adenosine A(1) receptor in anticonvulsant action of these drugs is doubtful.