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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 3

ADK immunoreactivity in hippocampus of control and TLE patients with medial temporal HS.

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ADK immunoreactivity in hippocampus of control and TLE patients with med...
(A–D) Sections were counterstained with hematoxylin. Shown are representative CA1 (A and B) and hilus (C and D) from the same sample. (A and C) Control hippocampus showed weak ADK immunoreactivity. Histologically normal surgical hippocampus displayed an immunoreactivity pattern similar to that in control autopsy hippocampus (not shown). (B and D) The HS specimen demonstrated increased ADK expression in both residual pyramidal and hilar neurons (arrows and B, top inset) and in reactive astrocytes (arrowheads and B, bottom inset). Insets in D show expression of ADK (red) in a reactive astrocyte (GFAP, green). Scale bars: 160 μm (A and B); 80 μm (C and D); 40 μm (A, inset, and B, top inset); 15 μm (B, bottom inset, and D, insets). (E and F) Western blot analysis of ADK of total homogenates from control autopsy hippocampus and HS specimens. (E) Representative immunoblots. (F) Densitometric data, expressed relative to optical density of β-actin (n = 5 per group). Data are mean ± SEM. *P < 0.05 vs. control.

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