The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury.
The postinjury period of glucose metabolic depression is accompanied by adenosine triphosphate decreases, increased flux of glucose through the pentose phosphate pathway, free radical production, activation of poly-ADP ribose polymerase via DNA damage, and inhibition of glyceraldehyde dehydrogenase (a key glycolytic enzyme) via depletion of the cytosolic NAD pool. Under these post-brain injury conditions of impaired glycolytic metabolism, glucose becomes a less favorable energy substrate. Ketone bodies are the only known natural alternative substrate to glucose for cerebral energy metabolism. While it has been demonstrated that other fuels (pyruvate, lactate, and acetyl-L-carnitine) can be metabolized by the brain, ketones are the only endogenous fuel that can contribute significantly to cerebral metabolism. Preclinical studies employing both pre- and postinjury implementation of the ketogenic diet have demonstrated improved structural and functional outcome in traumatic brain injury (TBI) models, mild TBI/concussion models, and spinal cord injury. Further clinical studies are required to determine the optimal method to induce cerebral ketone metabolism in the postinjury brain, and to validate the neuroprotective benefits of ketogenic therapy in humans.
Department of Neurosurgery, Brain Injury Research Center University of California, Los Angeles, Los Angeles, CA.
Mayumi L
ML
Prins
Department of Pediatrics, Division of Pediatric Neurology, University of California, Los Angeles, Los Angeles, CA.
Joyce H
JH
Matsumoto
D000818:Animals; D001924:Brain Concussion / Q000178:diet therapy / Q000378:metabolism / Q000628:therapy; D001930:Brain Injuries / Q000178:diet therapy* / Q000378:metabolism / Q000628:therapy; D002540:Cerebral Cortex / Q000293:injuries / Q000378:metabolism*; D055423:Diet, Ketogenic / Q000009:adverse effects; D019587:Dietary Supplements; D015536:Down-Regulation; D004734:Energy Metabolism; D019317:Evidence-Based Medicine; D006019:Glycolysis; D006801:Humans; D007262:Infusions, Intravenous; D060186:Infusions, Spinal; D007657:Ketone Bodies / Q000008:administration & dosage / Q000378:metabolism* / Q000627:therapeutic use; D007659:Ketones / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use; D009474:Neurons / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000178:diet therapy / Q000378:metabolism / Q000628:therapy
D007657:Ketone Bodies; D007659:Ketones
alternative substrates; neuroprotection; β-hydroxybutyrate