The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury

J Lipid Res. 2014 Dec;55(12):2450-7. doi: 10.1194/jlr.R046706. Epub 2014 Apr 10.


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.

Keywords: alternative substrates; neuroprotection; β-hydroxybutyrate.

Publication types

  • Review

MeSH terms

  • Animals
  • Brain Concussion / diet therapy
  • Brain Concussion / metabolism
  • Brain Concussion / therapy
  • Brain Injuries / diet therapy*
  • Brain Injuries / metabolism
  • Brain Injuries / therapy
  • Cerebral Cortex / injuries
  • Cerebral Cortex / metabolism*
  • Diet, Ketogenic* / adverse effects
  • Dietary Supplements
  • Down-Regulation
  • Energy Metabolism*
  • Evidence-Based Medicine*
  • Glycolysis
  • Humans
  • Infusions, Intravenous
  • Infusions, Spinal
  • Ketone Bodies / administration & dosage
  • Ketone Bodies / metabolism*
  • Ketone Bodies / therapeutic use
  • Ketones / administration & dosage
  • Ketones / metabolism
  • Ketones / therapeutic use
  • Neurons / metabolism*
  • Spinal Cord / metabolism
  • Spinal Cord Injuries / diet therapy
  • Spinal Cord Injuries / metabolism
  • Spinal Cord Injuries / therapy


  • Ketone Bodies
  • Ketones