Ketogenic diet attenuates post-cardiac arrest brain injury by upregulation of pentose phosphate pathway–mediated antioxidant defense in a mouse model of cardiac arrest

• Published in: Nutrition (Burbank, Los Angeles County, Calif.) Vol. 103-104; p. 111814
• Main Authors: Peng, Fei, Zhang, Yu-Han, Zhang, Lu, Yang, Man, Chen, Chan, Yu, Hai, Li, Tao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2022; Elsevier Limited
• Subjects: Adenine; Animals; Antioxidants; Antioxidants - metabolism; Apoptosis; Brain; Brain Injuries; Brain injury; Carbohydrates; Cardiac arrest; Cardiopulmonary resuscitation; Cell viability; Computed tomography; CPR; Deprivation; Diet; Diet, Ketogenic; Disease Models, Animal; Emission analysis; Glucose; Glucose - metabolism; Glucose 6 phosphate dehydrogenase; Glucosephosphate dehydrogenase; Glutathione; Glycolysis; Head injuries; Heart; Heart Arrest - complications; Heart Arrest - therapy; High fat diet; Ketogenesis; Ketogenic diet; Laboratory animals; Low carbohydrate diet; Magnetic resonance spectroscopy; Metabolism; Metabolites; Mice; NADP - genetics; NADP - metabolism; NADPH-diaphorase; Nicotinamide; Nicotinamide adenine dinucleotide; NMR; Nuclear magnetic resonance; Oxidation; Oxygen; Oxygen - metabolism; Pentose; Pentose phosphate pathway; Pentose Phosphate Pathway - genetics; Phenotypes; Phosphates; Positron emission; Positron emission tomography; Post-cardiac arrest brain injury; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Resuscitation; Spectrum analysis; Survival; Tomography; Traumatic brain injury; Up-Regulation; United States > US; China; Germany; Pentose phosphate pathway; Glucose metabolism; Post-cardiac arrest brain injury; Ketogenic diet; Cardiac arrest
• ISSN: 0899-9007; 1873-1244
• DOI: 10.1016/j.nut.2022.111814

[Display omitted] •Post-cardiac arrest brain injury can be attenuated by ketogenic diet.•Ketogenic diet suppresses glucose oxidation in the brain.•Ketogenic diet activates pentose phosphate pathway-mediated antioxidant system. The aim of this study was to investigate the effect of the ketogenic diet (KD) on post-cardiac arrest brain injury in a mouse model of cardiac arrest and cardiopulmonary resuscitation. Mice were fed a KD for 4 wk and then subjected to cardiac arrest and cardiopulmonary resuscitation. The HT22 cells after β-hydroxybutyrate (β-OHB) treatment were exposed to oxygen-glucose deprivation/reoxygenation. Survival and neurologic function were measured after return of spontaneous circulation. Positron emission tomography/computed tomography scanning, 13C-magnetic resonance spectroscopy analysis, and seahorse assay were performed to explore the mechanism underlying the phenotype. Results of this study demonstrated that KD improved neurologic function and reduced apoptotic neurons in cardiac arrest and cardiopulmonary resuscitation mice. With no alteration of glucose uptake, KD suppressed glucose oxidation in mouse brain. Consistently, the glycolytic capacity of the HT22 cells was also downregulated by β-OHB treatment. Moreover, KD increased nicotinamide adenine dinucleotide phosphate/oxidized nicotinamide adenine dinucleotide phosphate and reduced glutathione/oxidized glutathione couples and reduced reactive oxygen species in the brain, probably due to activation of glucose-6-phosphate dehydrogenase, the rate-limiting enzyme in the pentose phosphate pathway. Pharmacologic inhibition of pentose phosphate pathway totally abolished the influence of β-OHB on glycolysis, and post–oxygen-glucose deprivation/reoxygenation cell viability and reactive oxygen species production in HT22 cells. KD improved survival and attenuated post-cardiac arrest brain injury, which was mediated by upregulation of pentose phosphate pathway and related antioxidant defense system.