Effects of the Ketogenic Diet on the Blood–Brain Barrier

Abstract

AbstractThe ketogenic diet (KD) is considered a valuable nonpharmacologic approach for treating multiple neurologic disorders, for attenuating the neurologic sequelae of brain injury, and for reducing seizure burden. The mechanisms by which the KD works are largely unknown. Glucose is virtually the sole energy source for the brain. However, during times of starvation, the liver produces ketone bodies (KBs), which can supply up to 70% of the brain’s energy needs. Acetoacetate and β-hydroxybutyrate (βHB) are the most abundant KBs, whereas acetone, present in small quantities, is not commonly utilized as an energy source. Ketones are also advantageous in neuroinflammatory conditions because they decrease the production of free radicals. Studies suggest a significant increase in cerebral ketone uptake after brain injury. KBs are always present in the blood, and their levels increase after high-fat dietary intake, prolonged exercise, or extended fasting. Thus, one can predict an effect on the brain capillary endothelium from high levels of ketones in the blood. Prolonged exposure of blood–brain barrier (BBB) endothelial cells to KBs induces expression of monocarboxylate transporters and enhances the cerebral uptake rate of KBs. In addition, cell migration and expression of gap junction proteins are upregulated by KBs. Altogether, reports suggest that the beneficial effects of the KD may depend on increased brain uptake of KBs to match metabolic demand as well as repair of the disrupted BBB. As the effects of KBs on the BBB and transport mechanisms across the BBB are better understood, it will be possible to develop alternative strategies to optimize therapeutic benefits for brain disorders where the BBB is compromised.