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Suppression of kindling epileptogenesis by adenosine-releasing stem cell-derived brain implants
Epilepsy therapy is largely symptomatic and no effective therapy is available to prevent epileptogenesis. We set out to explore the potential of stem cell-derived brain implants to suppress the progressive development of seizures in the rat kindling-model. Embryonic stem (ES) cells, engineered to release the inhibitory neuromodulator adenosine by biallelic genetic disruption of the adenosine kinase gene (Adk-/-), and respective wild-type cells, were differentiated into neural precursor cells (NPs) and injected into the hippocampus of rats prior to kindling. Wild-type NP graft recipients were characterized by an initial delay of seizure development, while recipients of adenosine-releasing NPs displayed sustained protection from developing generalized seizures. The therapeutic effect of Adk-deficient NPs was due to graft-mediated adenosine release, since seizures could transiently be provoked after blocking adenosine A1 receptors. Histological analysis of NP implants at day 26 revealed cell clusters within the infrahippocampal cleft as well as intrahippocampal donor cells expressing mature neuronal markers. We conclude that ES cell-derived adenosine releasing brain implants can suppress seizure progression in the rat kindling-model. These findings depict ES cells as potential tool for cell-mediated delivery of therapeutic factors in the treatment of epilepsy.
Supported by the DFG, the Hertie Foundation, the NIH, the Good Samaritan Hospital Foundation and the Epilepsy Research Foundation's New Therapy Development Project.