Adenosine, Ketogenic Diet and Epilepsy: The Emerging Therapeutic Relationship Between Metabolism and Brain Activity

S Masino,M Kawamura Jr,L Pomeroy,C Wasser,D Ruskin

doi:10.2174/157015909789152164

S Masino, M Kawamura Jr + Show 3 more

Open Access

https://doi.org/10.2174/157015909789152164

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Journal: Current Neuropharmacology	Publication Date: Sep 1, 2009
Citations: 132	License type: cc-by

Affiliation: College Summit, Trinity College

Abstract

For many years the neuromodulator adenosine has been recognized as an endogenous anticonvulsant molecule and termed a “retaliatory metabolite.” As the core molecule of ATP, adenosine forms a unique link between cell energy and neuronal excitability. In parallel, a ketogenic (high-fat, low-carbohydrate) diet is a metabolic therapy that influences neuronal activity significantly, and ketogenic diets have been used successfully to treat medically-refractory epilepsy, particularly in children, for decades. To date the key neural mechanisms underlying the success of dietary therapy are unclear, hindering development of analogous pharmacological solutions. Similarly, adenosine receptor–based therapies for epilepsy and myriad other disorders remain elusive. In this review we explore the physiological regulation of adenosine as an anticonvulsant strategy and suggest a critical role for adenosine in the success of ketogenic diet therapy for epilepsy. While the current focus is on the regulation of adenosine, ketogenic metabolism and epilepsy, the therapeutic implications extend to acute and chronic neurological disorders as diverse as brain injury, inflammatory and neuropathic pain, autism and hyperdopaminergic disorders. Emerging evidence for broad clinical relevance of the metabolic regulation of adenosine will be discussed.

Highlights

Adenosine is a potent neuromodulatory purine present throughout the extracellular space of the central nervous system
A1 receptors are distributed widely [73] and A2A receptors are located preferentially in the basal ganglia and olfactory tubercle [169]. Both the A1 and A2 receptor subtypes are antagonized by caffeine, the most widely used psychoactive substance worldwide, and caffeine’s actions at adenosine A1 and A2A receptors in the central nervous system underlie its alerting, locomotor and cognitive effects [136]
Increasing adenosine improves sleep, decreases seizures and reduces anxiety – all physiological effects that could be achieved by a metabolic strategy such as a ketogenic diet and would improve quality of life significantly in persons and families affected by ASD

Summary

Introduction

Adenosine is a potent neuromodulatory purine present throughout the extracellular space of the central nervous system. Physiological conditions which offer both high ATP levels and increased extracellular adenosine are ideal for epilepsy and for many acute and chronic neurological disorders characterized by metabolic dysfunction and neuronal vulnerability or frank progressive neurodegeneration.

Results

Conclusion