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A ketogenic diet suppresses seizures in mice through adenosine A1 receptors
Susan A. Masino, … , Eleonora Aronica, Detlev Boison
Susan A. Masino, … , Eleonora Aronica, Detlev Boison
Published June 23, 2011
Citation Information: J Clin Invest. 2011;121(7):2679-2683. https://doi.org/10.1172/JCI57813.
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Brief Report

A ketogenic diet suppresses seizures in mice through adenosine A1 receptors

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Abstract

A ketogenic diet (KD) is a high-fat, low-carbohydrate metabolic regimen; its effectiveness in the treatment of refractory epilepsy suggests that the mechanisms underlying its anticonvulsive effects differ from those targeted by conventional antiepileptic drugs. Recently, KD and analogous metabolic strategies have shown therapeutic promise in other neurologic disorders, such as reducing brain injury, pain, and inflammation. Here, we have shown that KD can reduce seizures in mice by increasing activation of adenosine A1 receptors (A1Rs). When transgenic mice with spontaneous seizures caused by deficiency in adenosine metabolism or signaling were fed KD, seizures were nearly abolished if mice had intact A1Rs, were reduced if mice expressed reduced A1Rs, and were unaltered if mice lacked A1Rs. Seizures were restored by injecting either glucose (metabolic reversal) or an A1R antagonist (pharmacologic reversal). Western blot analysis demonstrated that the KD reduced adenosine kinase, the major adenosine-metabolizing enzyme. Importantly, hippocampal tissue resected from patients with medically intractable epilepsy demonstrated increased adenosine kinase. We therefore conclude that adenosine deficiency may be relevant to human epilepsy and that KD can reduce seizures by increasing A1R-mediated inhibition.

Authors

Susan A. Masino, Tianfu Li, Panos Theofilas, Ursula S. Sandau, David N. Ruskin, Bertil B. Fredholm, Jonathan D. Geiger, Eleonora Aronica, Detlev Boison

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Figure 1

Seizure suppression by KD depends on A1R activation.

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Seizure suppression by KD depends on A1R activation.
   
Representative ...
Representative EEG recordings from the CA3 of WT and transgenic mice reflect seizure distribution over a 1-hour time span (top traces) and individual seizures at higher resolution (1 minute; bottom traces). Asterisks in top traces denote the individual seizures chosen. Beginning and end of seizures are marked by vertical arrows. Traces from CD-fed animals showed baseline seizure activity in all mutants and lack of seizures in WT. KD almost completely abolished seizures in Adk-Tg mice; rare seizures were of reduced duration, as shown. KD reduced seizure activity in A1R+/– mice, had no effect in A1R–/– mice. Treatment with glucose or DPCPX reversed KD effects. See Table 1 for quantitation.
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