The uptake and metabolism of ketone bodies in brain have been of interest to researchers and clinicians for decades but how they affect the coupling of blood flow and glucose metabolism, especially during chronic ketotic conditions, remains unclear. Although glucose is considered the primary fuel for brain, ketones supplement brain metabolism, especially under conditions of glucose sparing, such as fasting, starvation or high fat-low carbohydrate diet. The enzymes for ketone metabolism and the monocarboxylate transporters at the blood brain barrier are known to increase with fasting or ketogenic diet. It is known that cerebral ischemia, such as stroke (induced by cardiac arrest and resuscitation), results in altered glucose metabolism, the reduction of intracellular energy metabolites such as ATP, ADP and phosphocreatine and the accumulation of metabolic intermediates, such as lactate and adenosine. Degree of recovery of neurologic function following stroke (oxidative stress) is limited by the ability of the central nervous system to recover from an ischemic event. Based on our experiences we have developed the working hypothesis that ketones are effective against pathology associated with oxidative stress and/or altered glucose metabolism. The rationale is ketosis stabilizes glucose metabolism through the normalization of redox (lactate/pyruvate ratio) in brain. One potential mechanism is that ketone body metabolism differs from glucose such that when oxidized, acetyl-CoA units enter the Krebs-TCA cycle at the level of citrate bypassing glycolysis (the step after pyruvate dehydrogenase complex which is often a metabolic block following oxidative stress) and through feed-back regulation is known to down regulate glycolytic rates at the level of citrate, phosphofructokinase or hexokinase. Another proposed mechanism may be that ketosis facilitates anaplerosis (replenishment of the Krebs-TCA cycle intermediates) after oxidative challenges, a mechanism for neuroprotection. To investigate the effects of ketosis on cerebral metabolic rate for glucose (CMRglu) imaging modalities, such as PET analysis, and an in vivo rat model of ketosis will be used to determine if ketosis improves CMRglu and metabolic outcome following cardiac arrest and resuscitation.

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Fasting, prolonged starvation or consumption of high fat-low carbohydrate diet (ketogenic diet) is known to result in ketosis and has been used for the treatment of intractable epilepsy, especially where the seizures are caused by insufficient glucose transport into the brain. Based on animal studies, ketosis has been suggested to possess neuroprotective properties against neurodegenerative diseases such as Alzheimer's, Parkinson's and recovery from focal stroke. However, there has been little progress in developing therapies that optimize ketosis as an approach to the medical treatment of neurodegenerative diseases, and, therefore, we would like to investigate the effects of ketosis on brain metabolism of glucose (CMRglu) using image (PET) analysis in ketotic rat and to determine if there is improved outcome following cardiac arrest and resuscitation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Mitler, Merrill
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Case Western Reserve University
Schools of Medicine
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