Differential effects of agents enhancing purinergic transmission upon the antielectroshock efficacy of carbamazepine, diphenylhydantoin, diazepam, phenobarbital, and valproate in mice

Abstract

L-phenylisopropyladenosine (L-PIA; a preferential A1 adenosine agonist-0.05 mg/kg) offered no protection against electroconvulsions in mice but potentiated the anticonvulsant action of diazepam and valproate against maximal electroshock-induced seizures, decreasing the respective ED50 values from 9.5 to 4.0 mg/kg and from 250 to 185 mg/kg. However, it remained without effect on the protective activity of phenobarbital, carbamazepine and diphenylhydantoin. 5'-N-ethylcarboxamidoadenosine (NECA; a preferential A2 adenosine agonist-0.5 mg/kg) potentiated the efficacy of valproate. On the other hand, NECA (1 mg/kg) diminished the anticonvulsant action of phenobarbital (ED50 was elevated from 16.5 to 20.5 mg/kg), possessing no effect upon the protective action of carbamazepine. In addition, papaverine (20 mg/kg) significantly enhanced the protective efficacy of valproate and up to 40 mg/kg remained without influence upon the protective action of carbamazepine. However, papaverine (20 and 40 mg/kg) inhibited the anticonvulsive potential of phenobarbital. In the light of the results obtained A1 and A2 adenosine receptor-mediated events seem to possess different influences upon the protective effects of antiepileptic drugs.

Homeostatic bioenergetic network regulation: a novel concept to avoid pharmacoresistance in epilepsy

“…Whereas activation of the A 1 R can contribute to the generation of a globally inhibited network with potent anticonvulsant downstream effects [75, 76], activation of the A 2A R can potentiate specific functions within the inhibited network and thereby improve the signal to noise ratio of signal transduction in neuronal networks [77]. [78]Although A 2A R activation can have pro-convulsive effects [76, 79] and may modify the efficacy of AEDs [80], it appears that the net-effects of combined A 1 R and A 2A R activation are anticonvulsant [81]. An additional layer of complexity in the net-effects of adenosine is afforded by a possible anticonvulsant role of the A 3 R [82] and its interaction with AEDs [83].…”

“…However, the systemic augmentation of adenosine receptor signaling as achieved in these studies was associated with cardiovascular and sedative side effects [75, 83]. Likewise, the potentiation of anticonvulsant activity of classical AEDs by adenosine receptor agonists was associated with neurotoxic and peripheral side effects in at least some studies [80, 83], while peripheral side effects have not routinely been investigated in other studies [87, 88]. Thus, in order to avoid peripheral side effects and to utilize adenosine signaling for antiepileptic therapy, different approaches are needed.…”

Influence of CGS 15943 A (a nonxanthine adenosine antagonist) on the protection offered by a variety of antiepileptic drugs against maximal electroshock-induced seizures in mice

“…Furthermore, adenosine ag- onists, preferably at A1 adenosine receptors, were documented to potentiate the protective efficacy of some antiepileptic drugs against electroconvulsions (Czuczwar et al, 1990 b). On the contrary, methylxanthine derivatives (i.e.…”