Abstracts

Rationale: Pharmacotherapy for epilepsy is limited by drug resistance and failure to prevent development and progression of epilepsy. Adenosine is an anticonvulsant with proven efficacy in pharmacoresistant epilepsy. Consequently, adenosine augmentation constitutes a rational approach for seizure control. Due to cardiovascular side effects of systemic adenosine augmentation, focal application becomes a necessity. Using two independent rat models, hippocampal kindling and systemic kainic acid (KA), we report on the therapeutic potential of novel silk-based polymers engineered to release adenosine. Methods: Silk-based polymers were engineered to release 250 or 1000 ng adenosine per day during a limited time span of 10 days. In the first study, rats were kindled by unilateral hippocampal electrical stimulation. Polymers releasing 1000 ng adenosine per day, or control polymers, were implanted into the ipsilateral infrahippocampal fissure either prior to onset of kindling or into fully kindled (stage 5) rats. In the second study, convulsive status epilepticus (SE) in young male rats was triggered by systemic administration of KA (12 mg/kg i.p.). At 9 weeks after SE all animals had experienced at least 10 spontaneous stage 4 or 5 seizures and the average seizure rate was 4.2 1.2 seizures per week. At this time polymers releasing 250 ng adenosine/day or control polymers were implanted into the lateral brain ventricles and animals were subjected to 4 weeks of continuous video-EEG. Results: In fully kindled rats, recipients of adenosine-releasing implants (N=5) were protected from generalized seizures (avg. seizure stage 0.2 0.5) over a period of 10 days corresponding to the duration of sustained adenosine release. To monitor seizure-development in the presence of adenosine, adenosine-releasing or control polymers were implanted prior to kindling. After 30 stimulations (4-8 days after implantation) control animals developed convulsive stage 5 seizures, whereas recipients of adenosine implants were protected. Kindling was resumed after 9 days to allow expiration of adenosine-release. During 30 additional stimulations, rats with adenosine-releasing implants gradually resumed kindling at seizure stages corresponding to those when kindling was initially suspended, while controls kindled at convulsive seizure stages. In the KA model, seizures in recipients of adenosine implants were almost completely suppressed (avg. number of seizures 0.6 0.5; N = 10) during the first week, while seizure frequency increased in controls. Remarkably, seizure suppression in recipients of adenosine-releasing implants was maintained far beyond polymer expiration (day 10) into week 4 indicating a disease-modifying effect of focal adenosine-delivery. Conclusions: We demonstrate that sustained focal adenosine release from silk-based brain implants is sufficient to suppress seizures in two rat models of epilepsy. In addition, suppression of kindling epileptogenesis and prolonged seizure suppression in the rat post status model suggest a novel disease modifying effect of focal adenosine delivery.