<b>β</b> -hydroxybutyrate enhances brain metabolism in normoglycemia and hyperglycemia, providing cerebroprotection in a mouse stroke model

Hyperglycemia in poorly controlled diabetes is widely recognized as detrimental to organ dysfunction. However, the acute effects of hyperglycemia on brain metabolism and function are not fully understood. The potential protective benefit of ketone bodies on mitochondrial function in the brain has also not been well characterized. Here, we evaluated the acute effects of hyperglycemia and β-hydroxybutyrate (BHB) on brain metabolism by employing a novel approach leveraging adenosine triphosphate (ATP)-dependence of bioluminescence originating from luciferin-luciferase activity. Oxygen consumption rate was measured in <i>ex vivo</i> live brain punches to further evaluate mitochondrial function. Our data demonstrate that brain metabolism in mice is affected by acute exposure to high glucose. This short-term effect of glucose exposure was reduced by co-administration with the ketone body BHB. Additionally, we investigated the functional relevance of BHB using an <i>in vivo</i> photothrombotic stroke model to assess its cerebroprotective effects in presence or absence of acute hyperglycemia. BHB significantly reduced infarct size in the brain stroke model, providing functional evidence for its protective role in the brain. These findings suggest that BHB may effectively mitigate the adverse effects of metabolic stress and ischemic events on brain metabolism and function.