1. ¹Department of Anatomy, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA
2. ²Department of Neurosurgery, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA

Correspondence: Dr MA Puchowicz, Department of Anatomy, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4930, USA. E-mail: map10@case.edu

Received 13 March 2008; Revised 17 June 2008; Accepted 18 June 2008; Published online 23 July 2008.

Abstract

Neuroprotective properties of ketosis may be related to the upregulation of hypoxia inducible factor (HIF)-1, a primary constituent associated with hypoxic angiogenesis and a regulator of neuroprotective responses. The rationale that the utilization of ketones by the brain results in elevation of intracellular succinate, a known inhibitor of prolyl hydroxylase (the enzyme responsible for the degradation of HIF-1) was deemed as a potential mechanism of ketosis on the upregulation of HIF-1. The neuroprotective effect of diet-induced ketosis (3 weeks of feeding a ketogenic diet), as pretreatment, on infarct volume, after reversible middle cerebral artery occlusion (MCAO), and the upregulation of HIF-1 were investigated. The effect of -hydroxybutyrate (BHB), as a pretreatment, via intraventricular infusion (4 days of infusion before stroke) was also investigated following MCAO. Levels of HIF-1 and Bcl-2 (anti-apoptotic protein) proteins and succinate content were measured. A 55% or 70% reduction in infarct volume was observed with BHB infusion or diet-induced ketosis, respectively. The levels of HIF-1 and Bcl-2 proteins increased threefold with diet-induced ketosis; BHB infusions also resulted in increases in these proteins. As hypothesized, succinate content increased by 55% with diet-induced ketosis and fourfold with BHB infusion. In conclusion, the biochemical link between ketosis and the stabilization of HIF-1 is through the elevation of succinate, and both HIF-1 stabilization and Bcl-2 upregulation play a role in ketone-induced neuroprotection in the brain.