Editors' ChoiceEpilepsy

Adenosine and Seizures—What’s the Big Fat Deal?

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Science Translational Medicine  20 Jul 2011:
Vol. 3, Issue 92, pp. 92ec113
DOI: 10.1126/scitranslmed.3002892

We have known that dietary modification can treat seizures for nearly 2500 years, from when Hippocrates described a patient who was cured after complete abstinence from food and drink. But it wasn’t until early in the 20th century that physicians found a more humane yet suitable substitute for starvation: a high-fat, low-carbohydrate diet capable of inducing ketogenesis—the production of ketone bodies from fatty acid breakdown. Now, this so-called ketogenic diet, which induces a switch from glucose- to ketone-based metabolism, is often prescribed for patients with epilepsy who do not respond to the available medications, and randomized control trials have confirmed the effectiveness of this lifestyle modification. Still, the mechanisms behind the improved clinical outcomes remained a mystery. In a recent study, Masino and colleagues shed new light on the molecular pathways that link a ketogenic diet with the suppression of seizure activity.

The functional interaction between adenosine and adenosine A1 receptors (A1Rs) sits at the center of this emerging story. Adenosine—the backbone of the energy-packed molecule adenosine 5'-triphosphate (ATP)—is known to be a potent anticonvulsant, and mice that are genetically modified to lack A1R and or to produce elevated concentrations of adenosine kinase (ADK)—the enzyme that clears adenosine—are prone to seizures. Masino and colleagues fed both kinds of transgenic mice a ketogenic diet. ADK-overexpressing mice were nearly cured of seizures. In contrast, the high-fat, low-carbohydrate diet was unable to reduce seizures in mice that lacked A1R, whereas mice with half the normal complement of A1R experienced a 50% reduction in seizures. These improvements were lost when mice given the ketogenic diet were treated with an A1R-selective antagonist. Furthermore, in response to the diet, expression of ADK in the brain was reduced. These data suggest that ketogenic diets work through a reduction in amount and activity of ADK, which essentially functions to increase brain adenosine concentrations.

To extend these findings to human epilepsy, the authors measured expression of ADK in brain specimens taken from patients with refractory seizures. Compared with normal controls, patients with epilepsy had markedly elevated amounts of ADK, providing evidence that the A1R-ADK pathway might operative in human seizure disorders. Although further studies are needed in human populations, Masino and colleagues have unearthed a mechanism for an observation that dates back to the 5th century B.C.E. and provide evidence that A1Rs might represent druggable targets for pharmacoresistant epilepsy. Although effective, ketogenic diets are difficult to tolerate, and a new pharmacological approach that offers the hope of improved outcomes with a less restrictive diet will likely be a more palatable option.

S. A. Masino et al., A ketogenic diet suppresses seizures in mice through adenosine A1 receptors. J. Clin. Invest. 121, 2679–2683 (2011). [Full Text]

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