Status epilepticus may be caused by loss of adenosine anticonvulsant mechanisms.
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 A1-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 10 mg/kg of the specific A1-adenosine antagonist 8-cyclopentyl-1,3-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 200 micrograms 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 N6-cyclohexyladenosine and N6-cyclopentyladenosine prior to stimulation suppressed the development of status epilepticus. N6-Cyclohexyladenosine was also effective in terminating status epilepticus after it had progressed for 20 min. The effects of a selective A2-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 Gi-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 GABAB antagonist, phaclofen, and a GABAB agonist, baclofen, were also tested in the recurrent stimulation model, as GABAB receptors are also coupled to the same subset of K+ channels as the A1-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 GABAA 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Young
D
D
Department of Pharmacology & Clinical Pharmacology, School of Medicine, University of Auckland, New Zealand.
Dragunow
M
M
D000241:Adenosine / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology; D003292:Convulsants / Q000008:administration & dosage / Q000494:pharmacology; D004558:Electric Stimulation; D018756:GABA Antagonists; D007276:Injections, Intraventricular; D008297:Male; D037342:Pertussis Toxin; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000187:drug effects; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013226:Status Epilepticus / Q000473:pathology / Q000503:physiopathology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D003292:Convulsants; D018756:GABA Antagonists; D018079:Receptors, GABA; D018047:Receptors, Purinergic P1; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D000241:Adenosine