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

Stroke is one of the leading causes of disability and death. Increasing evidence indicates that beta-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.

Automated summary

Moderate dose of BHB enhances mitochondrial complex I activity, reduces oxidative stress, inhibits mitochondrial apoptosis, improves neurological function, and decreases infarct volume in stroke. These effects are achieved by upregulating SMCT1 and activating the Erk/CREB/eNOS pathway. This study provides a novel understanding of the neuroprotective effects of BHB in stroke.