The Ketone Body, β-Hydroxybutyrate Stimulates the Autophagic Flux and Prevents Neuronal Death Induced by Glucose Deprivation in Cortical Cultured Neurons

Neurochem Res. 2016 Mar;41(3):600-9. doi: 10.1007/s11064-015-1700-4. Epub 2015 Aug 25.


Glucose is the major energy substrate in brain, however, during ketogenesis induced by starvation or prolonged hypoglycemia, the ketone bodies (KB), acetoacetate and β-hydroxybutyrate (BHB) can substitute for glucose. KB improve neuronal survival in diverse injury models, but the mechanisms by which KB prevent neuronal damage are still not well understood. In the present study we have investigated whether protection by the D isomer of BHB (D-BHB) against neuronal death induced by glucose deprivation (GD), is related to autophagy. Autophagy is a lysosomal-dependent degradation process activated during nutritional stress, which leads to the digestion of damaged proteins and organelles providing energy for cell survival. Results show that autophagy is activated in cortical cultured neurons during GD, as indicated by the increase in the levels of the lipidated form of the microtubule associated protein light chain 3 (LC3-II), and the number of autophagic vesicles. At early phases of glucose reintroduction (GR), the levels of p62 declined suggesting that the degradation of the autophagolysosomal content takes place at this time. In cultures exposed to GD and GR in the presence of D-BHB, the levels of LC3-II and p62 rapidly declined and remained low during GR, suggesting that the KB stimulates the autophagic flux preventing autophagosome accumulation and improving neuronal survival.

Keywords: Autophagy; Cortical cultures; Hypoglycemia; Ketone bodies; Neuronal death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxybutyric Acid / chemistry
  • 3-Hydroxybutyric Acid / metabolism*
  • 3-Hydroxybutyric Acid / pharmacology
  • Animals
  • Autophagy*
  • Cell Survival
  • Cells, Cultured
  • Cerebral Cortex / cytology*
  • Cerebral Cortex / metabolism
  • Glucose / metabolism*
  • Heat-Shock Proteins / metabolism
  • Microtubule-Associated Proteins / metabolism
  • Neurons / cytology*
  • Neurons / drug effects
  • Neurons / metabolism
  • Rats, Wistar
  • Sequestosome-1 Protein
  • Stereoisomerism


  • Heat-Shock Proteins
  • LC3 protein, rat
  • Microtubule-Associated Proteins
  • Sequestosome-1 Protein
  • Sqstm1 protein, rat
  • Glucose
  • 3-Hydroxybutyric Acid