Rational Application of β-Hydroxybutyrate Attenuates Ischemic Stroke by Suppressing Oxidative Stress and Mitochondrial-Dependent Apoptosis via Activation of the Erk/CREB/eNOS Pathway

ACS Chem Neurosci. 2021 Apr 7;12(7):1219-1227. doi: 10.1021/acschemneuro.1c00046. Epub 2021 Mar 19.


Stroke is one of the leading causes of disability and death. Increasing evidence indicates that β-hydroxybutyrate (BHB) exerts beneficial effects in treating stroke, but the underlying mechanism remains largely unknown. In this study, we injected different doses of BHB into the lateral ventricle in middle cerebral artery occlusion (MCAO) model rats and neuronal cells were treated with different doses of BHB followed by oxygen-glucose deprivation (OGD). We found that a moderate dose of BHB enhanced mitochondrial complex I respiratory chain complex I activity, reduced oxidative stress, inhibited mitochondrial apoptosis, improved neurological scores, and reduced infarct volume after ischemia. We further showed that the effects of BHB were achieved by upregulating the dedicated BHB transporter SMCT1 and activating the Erk/CREB/eNOS pathway. These results provide us with a foundation for a novel understanding of the neuroprotective effects of BHB in stroke.

Keywords: ROS; apoptosis; ischemia; mitochondrial; oxidative stress; stroke; β-Hydroxybutyrate.

MeSH terms

  • 3-Hydroxybutyric Acid / pharmacology
  • Animals
  • Apoptosis
  • Brain Ischemia* / drug therapy
  • Infarction, Middle Cerebral Artery / drug therapy
  • Ischemic Stroke*
  • Neuroprotective Agents* / pharmacology
  • Oxidative Stress
  • Rats
  • Stroke* / drug therapy


  • Neuroprotective Agents
  • 3-Hydroxybutyric Acid