Adenosine A1 receptor blockage mediates theophylline-associated seizures.
Theophylline-associated seizures (TAS) often progress to prolonged or treatment-resistant convulsions. Theophylline is a nonselective adenosine receptor antagonist. Adenosine is an endogenous anticonvulsant that can terminate seizures. Fever and young age have been reported to be risk factors for TAS. To elucidate the mechanism of TAS, we investigated the effect of theophylline and adenosine receptor ligands on hyperthermia-induced seizures in juvenile rats. The treatment dose of theophylline or control saline was injected intraperitoneally 1 h before hyperthermia-induced seizures. The seizure threshold in the theophylline group was significantly lower and seizure duration was significantly longer than those in the control group. The addition of a selective adenosine A(1) receptor agonist and an adenosine kinase inhibitor completely counteracted the effects of theophylline. Moreover, a selective A(1) antagonist caused a significantly longer seizure duration compared with the control. These findings suggest that blockage of the adenosine A(1) receptor is the main cause of TAS.
Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Ehime, Japan. fukumits@m.ehime-u.ac.jp
Mitsumasa
M
Fukuda
Yuka
Y
Suzuki
Hitomi
H
Hino
Kazuyo
K
Kuzume
Takehiko
T
Morimoto
Eiichi
E
Ishii
D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001831:Body Temperature / Q000502:physiology; D001921:Brain / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006979:Hyperthermia, Induced / Q000379:methods; D007274:Injections, Intraperitoneal; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D012640:Seizures / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D013806:Theophylline / Q000097:blood / Q000494:pharmacology*; D014372:Tubercidin / Q000031:analogs & derivatives / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D058916:Adenosine A1 Receptor Antagonists; D004791:Enzyme Inhibitors; C034214:5-iodotubercidin; C058394:2-chloro-N(6)cyclopentyladenosine; D013806:Theophylline; D000248:Adenosine Kinase; D000241:Adenosine; D014372:Tubercidin