ABSTRACT
Neuroprotective properties of ketosis may be related to the upregulation of hypoxia inducible factor (HIF)-1alpha, 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-1alpha) was deemed as a potential mechanism of ketosis on the upregulation of HIF-1alpha. 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-1alpha were investigated. The effect of beta-hydroxybutyrate (BHB), as a pretreatment, via intraventricular infusion (4 days of infusion before stroke) was also investigated following MCAO. Levels of HIF-1alpha 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-1alpha 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-1alpha is through the elevation of succinate, and both HIF-1alpha stabilization and Bcl-2 upregulation play a role in ketone-induced neuroprotection in the brain.
Subject(s)
Brain Edema/prevention & control , Brain Infarction/prevention & control , Brain Ischemia/diet therapy , Brain/metabolism , Diet, Ketogenic , Ketone Bodies/biosynthesis , Animals , Brain/enzymology , Brain Edema/enzymology , Brain Edema/metabolism , Brain Infarction/enzymology , Brain Infarction/metabolism , Brain Ischemia/enzymology , Brain Ischemia/metabolism , Disease Models, Animal , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Ketosis/metabolism , Male , Neuroprotective Agents/metabolism , Procollagen-Proline Dioxygenase/biosynthesis , Proto-Oncogene Proteins c-bcl-2/biosynthesis , RNA, Messenger/biosynthesis , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Succinic Acid/metabolismSubject(s)
Helicobacter Infections/immunology , Helicobacter Infections/prevention & control , Helicobacter pylori/immunology , Urease/immunology , Vaccination , Vaccines, DNA/administration & dosage , Vaccines, DNA/immunology , Animals , Bacterial Vaccines/administration & dosage , Bacterial Vaccines/immunology , HumansABSTRACT
It is recognized that brain oxygen deprivation results in increased glycolysis and lactate accumulation. Moreover, glucose metabolism is altered during starvation or diet, resulting in increased plasma ketones (acetoacetate + beta-hydroxybutyrate; BHB). We investigated glucose and lactate adaptation to hypoxia in concurrence with diet-induced ketosis. Male Wistar rats were fed standard (STD), ketogenic (high fat; KG), or carbohydrate-rich (low fat; CHO) diets for 3 wks and then exposed to hypobaric (0.5 ATM) or normobaric atmosphere for 3 wks while on their diets. Lactate, ketones, and glucose concentrations were measured in plasma (mM) and brain tissue (mmol/g). Plasma and tissue ketone levels were elevated up to 12-fold in the KG fed groups compared with other groups (STD and CHO), with the hypoxic KG group reaching the highest levels (2.6 +/- 1.3 mM and 0.3 +/- 0.1 mmol/g; mean +/- SD). Tissue lactate levels in the hypoxic ketotic rats (4.7 +/- 1.3 mM) were comparable with normoxic STD (5.0 +/- 0.7 mM) and significantly lower (ANOVA P < .05) than the hypoxic STD rats (6.1 +/- 1.0 mM). These data indicate that adaptation to hypoxia did not interfere with ketosis, and that ketosis during hypoxia may lower lactate levels in brain, suggesting decreased glycolysis or increased glucose disposal.