Adenosine, ketogenic diet and epilepsy: the emerging therapeutic relationship between metabolism and brain activity

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.

Keywords: Metabolism; addiction; autism; dopamine.; neurodegeneration; neuroprotection; pain; sleep.

Fig. (1)

The metabolic relationship between ketones and adenosine. Compounds upregulated by a ketogenic diet or exogenous ketones are italicized. (1) During ketolytic metabolism, the ketone bodies β-hydroxybutyrate (and its breakdown products acetone and acetoacetate) are either generated locally or hepatically and transported via the blood to other tissues (such as brain). Ketones are converted intracellularly into acetyl-CoA which enters the tricarboxylic acid cycle. (2) This mitochondrial energy cycle generates, at multiple steps (----), protons and electrons that are channeled to the electron transport chain by NADH and FADH2 (β-hydroxybutyrate conversion to acetoacetate also contributes). Many steps of the tricarboxylic acid cycle are omitted for simplicity. (3) The electron transport chain drives an electrochemical gradient across the mitochondrial outer membrane and ultimately oxidative phosphorylation which forms ATP from ADP and phosphate (P_i) by ATP synthase. (4) Enhanced ATP can be converted to phosphocreatine for energy storage, or broken down to its core molecule, adenosine. Adenosine levels inside and outside of the cell membrane are influenced concurrently by an equilibrative transporter. Due to the very large ATP / adenosine ratio inside the cell, a small increase in intracellular ATP could translate into a large relative increase in intracellular, and thus extracellular, adenosine.