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

Masino SA, Kawamura M, Wasser CD, Wasser CA, Pomeroy LT, Ruskin DN - Curr Neuropharmacol (2009)

Bottom Line: 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.To date the key neural mechanisms underlying the success of dietary therapy are unclear, hindering development of analogous pharmacological solutions.Emerging evidence for broad clinical relevance of the metabolic regulation of adenosine will be discussed.

View Article: PubMed Central - PubMed

Affiliation: Psychology Department, Trinity College, 300 Summit St., Hartford, CT, USA. susan.masino@trincoll.edu

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.

No MeSH data available.


Related in: MedlinePlus

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 (Pi) 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.
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Figure 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 (Pi) 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.

Mentions: Ketone bodies lead to energy production by conversion to acetyl-CoA which then enters the mitochondrial tricarboxylic acid cycle, replacing pyruvate (derived from glycolysis) as an acetyl-CoA source. The tricarboxylic acid cycle then leads as usual to proton flow out of the mitochondria matrix; this gradient in turn powers ATP production by ATP synthase in the mitochondrial inner membrane. Not only can ketone bodies substitute for glucose, metabolism of ketone bodies is more efficient than that of glucose, leading to more available energy for ATP synthesis. This effect derives from the higher heat of combustion of ketone bodies compared to pyruvate [187]; ketone body metabolism leads to reduction of the mitochondrial NAD couple (NAD+/NADH) and oxidation of the mitochondrial co-enzyme Q couple (Q/QH2). The difference between the redox potentials of these couples determines the magnitude of the proton gradient which in turn determines the free energy (ΔG’) of ATP hydrolysis – the increased difference with ketone body metabolism leads to increased ΔG’ for ATP production [187]. Key aspects of this energy cycle and its relationship to adenosine are summarized in Fig. (1).


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

Masino SA, Kawamura M, Wasser CD, Wasser CA, Pomeroy LT, Ruskin DN - Curr Neuropharmacol (2009)

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 (Pi) 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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2769009&req=5

Figure 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 (Pi) 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.
Mentions: Ketone bodies lead to energy production by conversion to acetyl-CoA which then enters the mitochondrial tricarboxylic acid cycle, replacing pyruvate (derived from glycolysis) as an acetyl-CoA source. The tricarboxylic acid cycle then leads as usual to proton flow out of the mitochondria matrix; this gradient in turn powers ATP production by ATP synthase in the mitochondrial inner membrane. Not only can ketone bodies substitute for glucose, metabolism of ketone bodies is more efficient than that of glucose, leading to more available energy for ATP synthesis. This effect derives from the higher heat of combustion of ketone bodies compared to pyruvate [187]; ketone body metabolism leads to reduction of the mitochondrial NAD couple (NAD+/NADH) and oxidation of the mitochondrial co-enzyme Q couple (Q/QH2). The difference between the redox potentials of these couples determines the magnitude of the proton gradient which in turn determines the free energy (ΔG’) of ATP hydrolysis – the increased difference with ketone body metabolism leads to increased ΔG’ for ATP production [187]. Key aspects of this energy cycle and its relationship to adenosine are summarized in Fig. (1).

Bottom Line: 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.To date the key neural mechanisms underlying the success of dietary therapy are unclear, hindering development of analogous pharmacological solutions.Emerging evidence for broad clinical relevance of the metabolic regulation of adenosine will be discussed.

View Article: PubMed Central - PubMed

Affiliation: Psychology Department, Trinity College, 300 Summit St., Hartford, CT, USA. susan.masino@trincoll.edu

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.

No MeSH data available.


Related in: MedlinePlus