Protection of hypoglycemia-induced neuronal death by β-hydroxybutyrate involves the preservation of energy levels and decreased production of reactive oxygen species

J Cereb Blood Flow Metab. 2015 May;35(5):851-60. doi: 10.1038/jcbfm.2015.1. Epub 2015 Feb 4.


Glucose is the main energy substrate in brain but in certain circumstances such as prolonged fasting and the suckling period alternative substrates can be used such as the ketone bodies (KB), beta-hydroxybutyrate (BHB), and acetoacetate. It has been shown that KB prevent neuronal death induced during energy limiting conditions and excitotoxicity. The protective effect of KB has been mainly attributed to the improvement of mitochondrial function. In the present study, we have investigated the protective effect of D-BHB against neuronal death induced by severe noncoma hypoglycemia in the rat in vivo and by glucose deprivation (GD) in cortical cultures. Results show that systemic administration of D-BHB reduces reactive oxygen species (ROS) production in distinct cortical areas and subregions of the hippocampus and efficiently prevents neuronal death in the cortex of hypoglycemic animals. In vitro results show that D-BHB stimulates ATP production and reduces ROS levels, while the nonphysiologic isomer of BHB, L-BHB, has no effect on energy production but reduces ROS levels. Data suggest that protection by BHB, not only results from its metabolic action but is also related to its capability to reduce ROS, rendering this KB as a suitable candidate for the treatment of ischemic and traumatic injury.

MeSH terms

  • 3-Hydroxybutyric Acid / pharmacology*
  • Acetoacetates / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Brain Injuries / drug therapy
  • Brain Injuries / metabolism
  • Brain Injuries / pathology
  • Brain Ischemia / drug therapy
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Cell Death / drug effects
  • Cells, Cultured
  • Cerebral Cortex* / metabolism
  • Cerebral Cortex* / pathology
  • Energy Metabolism / drug effects*
  • Glucose / metabolism
  • Hypoglycemia* / drug therapy
  • Hypoglycemia* / metabolism
  • Hypoglycemia* / pathology
  • Ketone Bodies / metabolism
  • Male
  • Neurons* / metabolism
  • Neurons* / pathology
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species / metabolism*


  • Acetoacetates
  • Ketone Bodies
  • Reactive Oxygen Species
  • acetoacetic acid
  • Adenosine Triphosphate
  • Glucose
  • 3-Hydroxybutyric Acid