Neuroprotection in Diet-Induced Ketotic Rat Brain after Focal Ischemia

Abstract

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

Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

“…43,44 In addition, it has recently been shown that the ketogenic diet and the infusion of BHB stabilize the hypoxia induced factor, which regulates the expression of genes involved in energy metabolism and antiapoptotic proteins such as Bcl-2. 7 It remains to be investigated whether these mechanisms are involved in the protective effect of BHB observed in the present experimental conditions. β-hydroxybutyrate reduces ROS during hypoglycemia A Julio-Amilpas et al…”

Ketosis Proportionately Spares Glucose Utilization in Brain

“…This process is not well understood but is thought to be highly associated with the duration and level of ketosis. 10,19,37,38 Ketones are considered to supply up to 70% of the total energy demands once maximal metabolic adaptation occurs. 1 Blood ketones become elevated during prolonged fasting or with a ketogenic diet reaching a state ketosis and glucose sparing.…”

“…16 Ketone bodies as neuroprotective agents appear to be related to the change in the regulation of the cell's stress responses, 17 as well as changes in oxidative (glucose) metabolism. 18,19 Neuroprotection by ketosis is thought to be associated with improved mitochondrial function, decreased reactive oxygen species, apoptotic and inflammatory mediators, and protective pathways. 9,20 In the last few decades, the 2-deoxy-D-glucose or positron emission tomography (PET) approaches have been applied to ketotic studies, in both animal, 18,[21][22][23] and humans.…”

The β-hydroxybutyrate receptor HCA2 activates a neuroprotective subset of macrophages

“…In clinical practice, ketogenic diet is now established in the treatment of pharmacoresistant childhood epilepsy. In addition, ketogenic diet and BHB exert a protective function in animal models of stroke, PD, AD and ALS [4][5][6][7][8] . So far small clinical trials suggest that it is also effective in neurodegenerative diseases 9 .…”