The role of adenosine in epilepsy

Adenosine is a well-characterized endogenous anticonvulsant and seizure terminator of the brain. Through a combination of adenosine receptor-dependent and -independent mechanisms, adenosine affects seizure generation (ictogenesis), as well as the development of epilepsy and its progression (epileptogenesis). Maladaptive changes in adenosine metabolism, in particular increased expression of the astroglial enzyme adenosine kinase (ADK), play a major role in epileptogenesis. Increased expression of ADK has dual roles in both reducing the inhibitory tone of adenosine in the brain, which consequently reduces the threshold for seizure generation, and also driving an increased flux of methyl-groups through the transmethylation pathway, thereby increasing global DNA methylation. Through these mechanisms, adenosine is uniquely positioned to link metabolism with epigenetic outcome. Therapeutic adenosine augmentation therefore not only holds promise for the suppression of seizures in epilepsy, but moreover the prevention of epilepsy and its progression overall. This review will focus on adenosine-related mechanisms implicated in ictogenesis and epileptogenesis and will discuss therapeutic opportunities and challenges.