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.
Susan A. Masino, Tianfu Li, Panos Theofilas, Ursula S. Sandau, David N. Ruskin, Bertil B. Fredholm, Jonathan D. Geiger, Eleonora Aronica, Detlev Boison
Title and authors | Publication | Year |
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Adenosine Kinase Deficiency in the Brain Results in Maladaptive Synaptic Plasticity
US Sandau, M Colino-Oliveira, A Jones, B Saleumvong, SQ Coffman, L Liu, C Miranda-Lourenco, C Palminha, VL Batalha, Y Xu, Y Huo, MJ Diogenes, AM Sebastiao, D Boison |
The Journal of neuroscience : the official journal of the Society for Neuroscience | 2016 |
The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine
D Boison |
Frontiers in molecular neuroscience | 2016 |
Dynamic Regulation of the Adenosine Kinase Gene during Early Postnatal Brain Development and Maturation
K Kiese, J Jablonski, D Boison, K Kobow |
Frontiers in molecular neuroscience | 2016 |
Metabolic Therapy for Temporal Lobe Epilepsy in a Dish: Investigating Mechanisms of Ketogenic Diet using Electrophysiological Recordings in Hippocampal Slices
MJ Kawamura, DN Ruskin, SA Masino |
Frontiers in molecular neuroscience | 2016 |
An Adenosine-Mediated Glial-Neuronal Circuit for Homeostatic Sleep
TE Bjorness, N Dale, G Mettlach, A Sonneborn, B Sahin, AA Fienberg, M Yanagisawa, JA Bibb, RW Greene |
The Journal of neuroscience : the official journal of the Society for Neuroscience | 2016 |
The ATP-sensitive K channel is seizure protective and required for effective dietary therapy in a model of mitochondrial encephalomyopathy
KJ Fogle, JI Hertzler, JH Shon, MJ Palladino |
Journal of Neurogenetics | 2016 |
Mechanisms of Action of Antiseizure Drugs and the Ketogenic Diet
MA Rogawski, W Löscher, JM Rho |
Cold Spring Harbor Perspectives in Medicine | 2016 |
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Boison D |
Current neuropharmacology | 2016 |