Suppression of kindled seizures by paracrine adenosine release from stem cell-derived brain implants

PURPOSE: Stem cells and their derivatives have emerged as a promising tool for cell-based drug delivery because of (a) their unique ability to differentiate into various somatic cell types, (b) the virtually unlimited donor source for transplantation, and (c) the advantage of being amenable to a wide spectrum of genetic manipulations. Previously, adenosine-releasing embryonic stem (ES) cells have been generated by disruption of both alleles of adenosine kinase (Adk-/-). Lack of ADK did not compromise the cells' differentiation potential into embryoid bodies or glial precursor cells. The aim of the present study was to investigate the potential of differentiated Adk-/- ES cell progeny for seizure suppression by paracrine adenosine release. METHODS: To isolate paracrine effects of stem cell-derived implants from effects caused by network integration, ES cell-derived embryoid bodies and glial precursor cells were encapsulated into semipermeable polymer membranes and grafted into the lateral brain ventricles of kindled rats. RESULTS: While seizure activity in kindled rats with wild-type Adk+/+ implants remained unaltered, rats with adenosine-releasing Adk-/- ES cell-derived implants displayed transient protection from convulsive seizures and a profound reduction of afterdischarge activity in EEG recordings. Long-term seizure suppression was precluded by limited viability of the encapsulated cells. CONCLUSIONS: We thereby provide a proof-of-principle that Adk-/- ES cell-derived brain implants can suppress seizure activity by a paracrine mode of action. Adk-deficient stem cells therefore represent a potential tool for the treatment of epileptic disorders.