Glycolytic inhibitor 2-deoxyglucose prevents cortical hyperexcitability after traumatic brain injury

JCI Insight. 2019 Apr 30;5(11):e126506. doi: 10.1172/jci.insight.126506.

Abstract

Traumatic brain injury (TBI) causes cortical dysfunction and can lead to post-traumatic epilepsy. Multiple studies demonstrate that GABAergic inhibitory network function is compromised following TBI, which may contribute to hyperexcitability and motor, behavioral, and cognitive deficits. Preserving the function of GABAergic interneurons, therefore, is a rational therapeutic strategy to preserve cortical function after TBI and prevent long-term clinical complications. Here, we explored an approach based on the ketogenic diet, a neuroprotective and anticonvulsant dietary therapy which results in reduced glycolysis and increased ketosis. Utilizing a pharmacologic inhibitor of glycolysis (2-deoxyglucose, or 2-DG), we found that acute in vitro application of 2-DG decreased the excitability of excitatory neurons, but not inhibitory interneurons, in cortical slices from naïve mice. Employing the controlled cortical impact (CCI) model of TBI in mice, we found that in vitro 2-DG treatment rapidly attenuated epileptiform activity seen in acute cortical slices 3 to 5 weeks after TBI. One week of in vivo 2-DG treatment immediately after TBI prevented the development of epileptiform activity, restored excitatory and inhibitory synaptic activity, and attenuated the loss of parvalbumin-expressing inhibitory interneurons. In summary, 2-DG may have therapeutic potential to restore network function following TBI.

Keywords: Epilepsy; Neurological disorders; Neuroscience.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antimetabolites / pharmacology*
  • Brain Contusion / metabolism
  • Brain Injuries, Traumatic / metabolism*
  • Cerebral Cortex / drug effects*
  • Cerebral Cortex / metabolism
  • Cortical Excitability / drug effects*
  • Deoxyglucose / pharmacology*
  • Diet, Ketogenic
  • Disease Models, Animal
  • Epilepsy, Post-Traumatic / metabolism*
  • GABAergic Neurons / drug effects*
  • GABAergic Neurons / metabolism
  • Glycolysis / drug effects*
  • In Vitro Techniques
  • Interneurons / drug effects
  • Interneurons / metabolism
  • Mice
  • Neural Inhibition / drug effects
  • Parvalbumins / metabolism

Substances

  • Antimetabolites
  • Parvalbumins
  • Deoxyglucose