Ketone Body Improves Neurological Outcomes after Cardiac Arrest by Inhibiting Mitochondrial Fission in Rats

Abstract

Ketone bodies including β-hydroxybutyrate (β-HB) have been proved the therapeutic potential in diverse neurological disorders. However, the role of β-HB in the regulation of neurological injury after cardiac arrest (CA) remains unclear. We investigated the effect of β-HB on brain mitochondrial dysfunction and neurological function after CA. A rat model of CA was established by asphyxia. The rats were randomly divided into three groups: sham group, control group, and β-HB group. Animals received 200 mg/kg β-HB or same volume vehicle at 10 minutes after return of spontaneous circulation by intraperitoneal injection. Neurological function was evaluated by neurologic deficit score and Y-maze. Neuronal cell loss and apoptosis were detected through hematoxylin-eosin staining, Nissl staining, and TdT-mediated dUTP nick-end labeling assay. Oxidative stress levels were determined by immunohistochemical staining of 4-hydoxynonenal and 8-hydroxy-2 ${}^{\prime }$ -deoxyguanosine. Furthermore, mitochondrial ultrastructure of brain cells was observed by transmission electron microscopy. In addition, the protein expression levels of Bak, caspase 3, gasdermin D, caspase 1, brain-derived neurotrophic factor, dynamin-related protein 1 (Drp1), and phospho-Drp1 (ser616) were measured. We found that neurological function and survival rate were significantly higher in the β-HB group compared with the control group. β-HB also reduced neurons death and neurological oxidative stress after CA. Moreover, β-HB reduced neurological injury from apoptosis and pyroptosis after CA. In addition, β-HB maintained the structural integrity of brain mitochondria, prevented mitochondrial fission, and increased brain energy metabolism after CA. In conclusion, β-HB beneficially affected the neurological function of rats after global cerebral ischemia, associated with decreased mitochondrial fission, and improved mitochondrial function. Our results suggest that β-HB might benefit patients suffering from neurological dysfunction after CA.