Status epilepticus may be caused by loss of adenosine anticonvulsant mechanisms

Abstract

The inhibitory neuromodulator adenosine is an endogenous anticonvulsant that terminates brief seizures in the brain and it has been proposed that loss of adenosine or adenosine-mediating systems may play a major role in the development of status epilepticus, a seizure condition characterized by prolonged and/or recurrent seizures that last by definition, at least 20 min. In this study, the effect of specific A 1-adenosine agonists and antagonists were tested for their ability to prevent and cause status epilepticus in two electrical stimulation models in rats. In a recurrent electrical stimulation model, whereas no vehicle-treated animals developed status epilepticus after 20 recurrent electrical stimulations, rats injected with 10mg/kg of the specific A 1-adenosine antagonist 8-cyclopentyl-l,3-dimethylxanthine intraperitoneally developed status epilepticus after stimulation. 8-( p-Sulphophenyl])-theophylline, which has limited penetrability into the brain when administered peripherally, did not cause status epilepticus when injected intraperitoneally. However, when 200μ g of 8-( p-sulphophenyl)-theophylline were administered intracerebroventricularly, status epilepticus developed in all animals, suggesting status epilepticus developed as a result of central adenosine receptor antagonism. In the second study, whereas all vehicle-treated animals developed status epilepticus after constant electrical stimulation, administration of NA 6-cyclohexyladenosine and N 6-cyclopentyladenosine prior to stimulation suppressed the development of status epilepticus. N 6-Cyclohexyladenosine was also effective in terminating status epilepticus after it had progressed for 20 min. The effects of a selective A 2-agonist was also tested on both stimulation models and had no anticonvulsant effects. An electrical stimulus given to rats pretreated three days prior to stimulation with pertussis toxin, a compound which inactivates G 1-proteins, also resulted in generalized status epilepticus, suggesting that impairment of G-protein-linked receptors is involved in the development of status epilepticus. The effects of a GABA B antagonist, phaclofen, and a GABA B agonist, baclofen, were also tested in the recurrent stimulation model, as GABA B receptors are also coupled to the same subset of K + channels as the A 1-receptor. Rats given phaclofen did not develop status epilepticus after recurrent electrical stimulation, although baclofen was effective at preventing the induction of status epilepticus in the constant stimulation model. These results, together with some preliminary data obtained showing that the GABA A antagonist picrotoxin did not cause status epilepticus after recurrent stimulation, suggest that loss of GABAergic inhibition only has a minor role in status epilepticus development in our models. Brains from all animals were also assessed for brain injury. There was a massive bilateral loss of nerve cells in the CA1 and CA3 regions of the hippocampus in 8-cyclopentyl-l,3-dimethylxanthine-injected rats that developed status epilepticus when compared with vehicle-injected rats or animals that had the 8-cyclopentyl-l, 3-dimethylxanthine/ N 6-cyclohexyladenosine drug combinations that did not develop status epilepticus. Rats that developed status epilepticus in the constant electrical stimulation model also showed the same pattern of cell loss in the hippocampus, although sometimes the loss was more concentrated on the side of stimulation. Animals that did not develop status epilepticus as a result of prior treatment with N 6-cyclohexyladenosine showed no cell damage. The results obtained in these studies provide strong support for the hypothesis that status epilepticus could result from a loss or impairment of the adenosine seizure termination mechanism. Furthermore, brain injury occurring during status epilepticus may involve adenosine mechanisms.