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Ketone Bodies, Potential Therapeutic Uses


Ketone Bodies, Potential Therapeutic Uses

Ketone Bodies, Potential Therapeutic Uses
Richard L. Veech, Britton Chance, Yoshihiro Kashiwaya, Henry A. Lardy, George F. Cahill Jr

Keywords
D-BETA-HYDROXYBUTYRATE • Ketone • Bodies • Ketosis • Metabolic • Control • Analysis • Neurologic • Disease

Abstract
Ketosis, meaning elevation of D- -hydroxybutyrate ( R -3-hydroxybutyrate) and acetoacetate, has been central to starving man's survival by providing nonglucose substrate to his evolutionarily hypertrophied brain, sparing muscle from destruction for glucose synthesis. Surprisingly, D- -hydroxybutyrate (abbreviated OHB) may also provide a more efficient source of energy for brain per unit oxygen, supported by the same phenomenon noted in the isolated working perfused rat heart and in sperm. It has also been shown to decrease cell death in two human neuronal cultures, one a model of Alzheimer's and the other of Parkinson's disease. These observations raise the possibility that a number of neurologic disorders, genetic and acquired, might benefit by ketosis. Other beneficial effects from OHB include an increased energy of ATP hydrolysis ( G') and its linked ionic gradients. This may be significant in drug-resistant epilepsy and in injury and anoxic states. The ability of OHB to oxidize co-enzyme Q and reduce NADP + may also be important in decreasing free radical damage. Clinical maneuvers for increasing blood levels of OHB to 2-5 mmol may require synthetic esters or polymers of OHB taken orally, probably 100 to 150 g or more daily. This necessitates advances in food-science technology to provide at least enough orally acceptable synthetic material for animal and possibly subsequent clinical testing. The other major need is to bring the technology for the analysis of multiple metabolic phenotypes up to the level of sophistication of the instrumentation used, for example, in gene science or in structural biology. This technical strategy will be critical to the characterization of polygenic disorders by enhancing the knowledge gained from gene analysis and from the subsequent steps and modifications of the protein products themselves.
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