Ketone Body Improves Neurological Outcomes after Cardiac Arrest by Inhibiting Mitochondrial Fission in Rats
Yunke Tan, Jie Zhang, Qiulin Ge, Xiangshao Fang, Fengqing Song, Tao Yu, Longyuan Jiang, Yongli Wei, Peng Wang
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 ′ ‐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.