Abstracts

Summary: The focus of this workshop is recent translational research on the purine ribonucleoside adenosine, which is an endogenous anticonvulsant of the brain with demonstrated efficacy in pharmacoresistant epilepsy. Although it has been known for 30 years that endogenously released adenosine regulates excitability in the hippocampus (1), only the advent of new molecular tools within the past 10 years has spawned a new era of translational research on adenosine. Recently, non-neuronal, in particular glial, mechanisms have received much attention for their pathogenetic role in epilepsy. Studies performed in genetically engineered mice have demonstrated that synaptic levels of adenosine, and thus hippocampal excitability, are largely regulated by astrocytes (2,3). It has further been demonstrated that astrogliosis and astrocyte dysfunction - pathogenetic hallmarks of the epileptic brain - directly affect adenosine signalling and hippocampal excitability. Findings that adenosine dysfunction is involved in the pathogenesis of epilepsy provide a direct neurochemical rationale for therapeutic intervention. Novel polymer-, stem cell- and gene- based approaches have demonstrated that focal adenosine augmentation is an effective strategy to suppress seizures in models of epilepsy (4) and recent findings suggest that therapeutic benefits of a ketogenic diet are at least partly mediated by an adenosine-related mechanism (5). Tom Swanson will provide a general introduction into the role of adenosine within the context of epilepsy and will provide a Clinician s perspective of this timely topic. Phil Haydon will discuss the role of astrocytes in regulating adenosine levels and seizure susceptibility. Susan Masino will conclude with novel adenosine-based therapeutic approaches that include the ketogenic diet and focal adenosine augmentation approaches. The expected outcome of this workshop is a detailed understanding how adenosine function and dysfunction are involved in the regulation of ictogenesis and epileptogenesis and how those findings can be translated into adenosine-based therapeutic strategies. 1. Dunwiddie TV: Endogenously released adenosine regulates excitability in the in vitro hippocampus, Epilepsia 1980, 21:541-548 2. Pascual O, Casper KB, Kubera C, Zhang J, Revilla-Sanchez R, Sul JY, Takano H, Moss SJ, McCarthy K, Haydon PG: Astrocytic purinergic signaling coordinates synaptic networks, Science 2005, 310:113-116 3. Li T, Ren G, Lusardi T, Wilz A, Lan JQ, Iwasato T, Itohara S, Simon RP, Boison D: Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice, J Clin Inv 2008, 118:571-582 4. Ren G, Li T, Lan JQ, Wilz A, Simon RP, Boison D: Lentiviral RNAi-induced downregulation of adenosine kinase in human mesenchymal stem cell grafts: a novel perspective for seizure control., Exp Neurol 2007, 208:26-37 5. Kawamura M, Jr., Ruskin DN, Masino SA: Metabolic autocrine regulation of neurons involves cooperation among pannexin hemichannels, adenosine receptors, and KATP channels, J Neurosci 2010, 30:3886-3895