Seizure suppression by adenosine A1 receptor activation in a mouse model of pharmacoresistant epilepsy.
OBJECTIVE
Because of the high incidence of pharmacoresistance in the treatment of epilepsy (20-30%), alternative treatment strategies are needed. Recently a proof-of-principle for a new therapeutic approach was established by the intraventricular delivery of adenosine released from implants of engineered cells. Adenosine-releasing implants were found to be effective in seizure suppression in a rat model of temporal lobe epilepsy. In the present study, activation of the adenosine system was applied as a possible treatment for pharmacoresistant epilepsy.


METHODS
A mouse model for drug-resistant mesial temporal lobe epilepsy was used, in which recurrent spontaneous seizure activity was induced by a single intrahippocampal injection of kainic acid (KA; 200 ng in 50 nl).


RESULTS
After injection of the selective adenosine A1-receptor agonist, 2-chloro-N6-cyclopentyladenosine (CCPA; either 1.5 or 3 mg/kg, i.p.), epileptic discharges determined in EEG recordings were completely suppressed for a period of </=3.5 h after the injections. Seizure suppression was maintained when 8-sulfophenyltheophylline (8-SPT), a non-brain-permeable adenosine-receptor antagonist, was coinjected systemically with CCPA. In contrast, systemic injection of carbamazepine or vehicle alone did not alter the seizure pattern.


CONCLUSIONS
This study demonstrates that activation of central adenosine A1 receptors leads to the suppression of seizure activity in a mouse model of drug-resistant epilepsy. We conclude that the local delivery of adenosine into the brain is likely to be effective in the control of intractable seizures.
Gouder
Nicolette
N
Institute of Pharmacology and Toxicology, University of Zurich, Switzerland.
Fritschy
Jean-Marc
JM
Boison
Detlev
D
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004569:Electroencephalography / Q000187:drug effects*; D004833:Epilepsy, Temporal Lobe / Q000139:chemically induced / Q000503:physiopathology*; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007267:Injections; D007608:Kainic Acid; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1 / Q000502:physiology; D013702:Temporal Lobe / Q000187:drug effects / Q000503:physiopathology
D000927:Anticonvulsants; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; C058394:2-chloro-N(6)cyclopentyladenosine; D000241:Adenosine; D007608:Kainic Acid