Effect of an adenosine antagonist and an adenosine agonist on status entry and severity in a model of limbic status epilepticus.
Adenosine is an endogenous neuromodulator that suppresses excitatory neurotransmission. We postulated that adenosine-mediated mechanisms resist status epilepticus (SE) entry and limit SE severity. In the first experiment rats were given an adenosine agonist (2-chloroadenosine), an adenosine antagonist (aminophylline), or saline vehicle, prior to SE induction with pulsed-train current delivered to amygdala in successive 5-min current-on sessions. Saline-treated animals entered limbic SE, with predominantly exploratory behavior, after 6.0 +/- 0.9 current-on sessions. Aminophylline increased major convulsive activity during stimulation and resulted in entry into convulsive SE after only 2.1 +/- 0.1 sessions. 2-Chloroadenosine, in contrast, suppressed major convulsive activity during stimulation, and blocked (in 3/7) or delayed (4/7) SE entry, with successes requiring 12.8 +/- 0.9 stimulation sessions. In a second experiment, animals already in exploratory SE were administered a single injection of saline vehicle, aminophylline, or 2-chloroadenosine. Aminophylline converted exploratory SE into lethally severe convulsive SE. 2-Chloroadenosine suppressed SE behaviorally and electrographically, and protected recipients from the seizure-associated cerebral damage seen in saline-administered SE controls. These results support the hypothesis that endogenous adenosine mechanisms resist SE entry, modulate the severity of ongoing SE, and limit the anatomic spread of seizure activity.
Handforth
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Department of Veterans Affairs Medical Center, West Los Angeles, CA.
Treiman
D M
DM
D015762:2-Chloroadenosine / Q000494:pharmacology; D000241:Adenosine / Q000037:antagonists & inhibitors* / Q000502:physiology*; D000628:Aminophylline / Q000494:pharmacology; D000679:Amygdala / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004558:Electric Stimulation; D004569:Electroencephalography / Q000187:drug effects; D017029:Epilepsy, Complex Partial / Q000473:pathology / Q000503:physiopathology; D008032:Limbic System / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*
D015762:2-Chloroadenosine; D000628:Aminophylline; D000241:Adenosine