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Commentary Adenosine is a purine nucleoside that modulates many physiologic processes, playing pivotal roles in biochemical pathways, signal transduction cascades, and inhibitory neurotransmission, and it even mediates cellular protection in the CNS. Two primary receptors bind adenosine, the ubiquitous inhibitory adenosine A1 receptor (A1R), and the less abundant excitatory A2ARs. The most recognizable role of adenosine is that involving the stimulant caffeine, which counteracts the inhibitory effects of adenosine. Due to its broad inhibitory action, adenosine has long been thought of as an endogenous anticonvulsant, and hence enhancement of purinergic activity would be expected to counter seizure activity (1). However, despite compelling laboratory evidence (2, 3), there is as yet no clinical evidence demonstrating that adenosine induces direct anticonvulsant effects. Further, none of the currently utilized anticonvulsant medications are believed to exert their clinical effects through modulation of purinergic neurotransmission. Interestingly, however, allopurinol (a structural isomer of hypoxanthine and a naturally occurring purine in the body used primarily to treat hyperuricemia) has been shown recently in a double-blind, placebo-controlled trial to provide anticonvulsant effects in humans when used adjunctively to treat medically refractory epilepsy (4). Further, a deficit in A1R expression has been observed in surgically resected specimens from patients with temporal lobe epilepsy (5), although it is difficult to determine whether such changes are causally linked to seizure genesis or a consequence of the epileptic state (6). Nevertheless, the concept that adenosine may be important to anticonvulsant activity has been strengthened over the past few years by a series of intriguing research studies and hypothesis papers linking this important substrate to the ketogenic diet (KD) (1, 7, 8). Masino and colleagues reasoned that adenosine could be a critical player in KD action because of the following observations: 1) adenosine is a powerful endogenous CNS depressant whose levels are influenced by dietary manipulation; 2) deletion of A1Rs and enhanced adenosine clearance by increases in adenosine kinase (ADK)—the major adenosine-metabolizing enzyme—both cause spontaneous electrographic seizures in hippocampus (9); 3) adenosine represents the core structural moiety for the all-important energy molecule ATP, which among other actions maintains ionic gradients across the neuronal cell membrane (i.e., through Na-K-ATPase activity); and 4) the anticonvulsant KD has been shown to raise levels of energy substrates in animals (10). Earlier, these investigators found that a component feature of KD treatment—that is, glucose restriction—led to ATP release through pannexin hemichannels localized to CA3 hippocampal neurons (8). The increased extracellular ATP, upon rapid degradation by ectonucleotidases to adenosine, resulted A Ketogenic Diet Suppresses Seizures in Mice Through Adenosine A1 Receptors.

Adenosine: A Fundamental Factor Formed from Fatty Feasts for Fighting Fits?