Purpose: 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.