A ketogenic diet suppresses seizures in mice through adenosine A(1) receptors

作者：Masino Susan A; Li Tianfu; Theofilas Panos; Sandau Ursula S; Ruskin David N; Fredholm Bertil B; Geiger Jonathan D; Aronica Eleonora; Boison Detlev^*

来源：Journal of Clinical Investigation, 2011, 121(7): 2679-2683.

DOI：10.1172/JCI57813

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 A(1) receptors (A(1)Rs). 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 A(1)Rs, were reduced if mice expressed reduced A(1)Rs, and were unaltered if mice lacked A(1)Rs. Seizures were restored by injecting either glucose (metabolic reversal) or an AIR 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 AIR-mediated inhibition.

• 出版日期2011-7