Adenosine augmentation therapies (AATs) for epilepsy: Prospect of cell and gene therapies

Deficiencies in the brain's own adenosine-based seizure control system contribute to seizure generation. Consequently, reconstitution of adenosinergic neuromodulation constitutes a rational approach for seizure control. This review will critically discuss focal adenosine augmentation strategies and their potential for antiepileptic and disease modifying therapy. Due to systemic side effects of adenosine focal adenosine augmentation - ideally targeted to an epileptic focus - becomes a therapeutic necessity. This has experimentally been achieved in kindled seizure models as well as in post-status epilepticus models of spontaneous recurrent seizures using three different therapeutic strategies that will be discussed here: (i) polymer-based brain implants that were loaded with adenosine; (ii) brain implants comprised of cells engineered to release adenosine and embedded in a cell-encapsulation device; (iii) direct transplantation of stem cells engineered to release adenosine. To meet the therapeutic goal of focal adenosine augmentation, genetic disruption of the adenosine metabolizing enzyme adenosine kinase (ADK) in rodent and human cells was used as a molecular strategy to induce adenosine release from cellular brain implants, which demonstrated antiepileptic and neuroprotective properties. New developments and therapeutic challenges in using AATs for epilepsy therapy will critically be evaluated.