Neuroprotective Properties of Ketone Bodies

Abstract

Ketosis, as with fasting or induced by ketogenic diet, continues to be explored as a strategy toward the treatment of neuropathologies and disease. Exogenous administration of anaplerotic compounds has shown promise as they rescue oxidatively stressed tissues and has shown to improve overall function in liver and heart, but little is known about their application in brain. Precursors of propionyl-CoA such as odd-chain fatty acids (propionate, heptanoate) as well as odd-chain C4 and C5 have been changed to C₄ and C₅ consistently. Please check.C₅-ketone bodies (β-keto and R-β-hydroxypentanoate) are potential anaplerotic substrates as these compounds are metabolized to propionyl-CoA that enters the citric acid cycle as succinyl-CoA. We have recently reported that ketosis was neuroprotective against transient focal ischemia. In this study, we present data that support the use of alternate energy substrates such as propionate and ketone bodies, as part of treatment regimes against ischemia–reperfusion injury. We propose that anaplerotic compounds are beneficial to recovery of brain following an ischemic event, such as with transient global or focal brain ischemia. We present data from two in vivo models of transient brain ischemia, cardiac arrest and resuscitation and focal stroke (via MCAO) where either ketosis induced by ketogenic diet (C₄ ketosis) or infusion of propionate ester (N,S-dipropionyl cysteine ethyl ester) resulted in improved outcome following ischemic insult.