For many years the
neuromodulator adenosine has been recognized as an endogenous
anticonvulsant molecule and termed a "retaliatory metabolite." As the core molecule of
ATP,
adenosine forms a unique link between cell energy and neuronal excitability. In parallel, a ketogenic (high-fat,
low-carbohydrate) diet is a metabolic
therapy that influences neuronal activity significantly, and
ketogenic diets have been used successfully to treat medically-
refractory epilepsy, particularly in children, for decades. To date the key neural mechanisms underlying the success of dietary
therapy are unclear, hindering development of analogous pharmacological solutions. Similarly,
adenosine receptor-based
therapies for
epilepsy and myriad other disorders remain elusive. In this review we explore the physiological regulation of
adenosine as an
anticonvulsant strategy and suggest a critical role for
adenosine in the success of
ketogenic diet therapy for
epilepsy. While the current focus is on the regulation of
adenosine, ketogenic metabolism and
epilepsy, the therapeutic implications extend to acute and chronic
neurological disorders as diverse as
brain injury, inflammatory and
neuropathic pain,
autism and hyperdopaminergic disorders. Emerging evidence for broad clinical relevance of the metabolic regulation of
adenosine will be discussed.