Chronic inhibition of brain glycolysis initiates epileptogenesis

J Neurosci Res. 2017 Nov;95(11):2195-2206. doi: 10.1002/jnr.24019. Epub 2017 Feb 2.


Metabolic abnormalities found in epileptogenic tissue provide considerable evidence of brain hypometabolism, while major risk factors for acquired epilepsy all share brain hypometabolism as one common outcome, suggesting that a breakdown of brain energy homeostasis may actually precede epileptogenesis. However, a causal link between deficient brain energy metabolism and epilepsy initiation has not been yet established. To address this issue we developed an in vivo model of chronic energy hypometabolism by daily intracerebroventricular (i.c.v.) injection of the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) and also investigated acute effects of 2-DG on the cellular level. In hippocampal slices, acute glycolysis inhibition by 2-DG (by about 35%) led to contrasting effects on the network: a downregulation of excitatory synaptic transmission together with a depolarization of neuronal resting potential and a decreased drive of inhibitory transmission. Therefore, the potential acute effect of 2-DG on network excitability depends on the balance between these opposing pre- and postsynaptic changes. In vivo, we found that chronic 2-DG i.c.v. application (estimated transient inhibition of brain glycolysis under 14%) for a period of 4 weeks induced epileptiform activity in initially healthy male rats. Our results suggest that chronic inhibition of brain energy metabolism, characteristics of the well-established risk factors of acquired epilepsy, and specifically a reduction in glucose utilization (typically observed in epileptic patients) can initiate epileptogenesis. © 2017 Wiley Periodicals, Inc.

Keywords: 2-deoxy-D-glucose; energy metabolism; epilepsy; glucose utilization; hippocampus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / physiopathology*
  • Deoxyglucose / administration & dosage
  • Energy Metabolism / drug effects
  • Energy Metabolism / physiology*
  • Epilepsy / metabolism*
  • Epilepsy / physiopathology*
  • Glycolysis / drug effects
  • Glycolysis / physiology*
  • Injections, Intraventricular
  • Male
  • Mice
  • Organ Culture Techniques
  • Rats
  • Rats, Sprague-Dawley


  • Deoxyglucose