Energy Balance During Ketosis in Rat Brain

大鼠大脑酮症期间的能量平衡

• 批准号: 7812117
• 负责人: Joseph Charles Lamanna
• 金额: $ 19.43万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812117
• 关键词: Acetates; Acetyl Coenzyme A; Acute; Address; Adenosine; Affect; Alzheimer' s Disease; Animals; Apoptosis; Astrocytes; Back; Blood; Blood - brain barrier anatomy; Blood flow; Brain; Bypass; Carbohydrates; Carbon; Cerebral Ischemia; Cerebrum; Cessation of life; Chronic; Citrates; Citric Acid Cycle; Consumption; Coupling; Defect; Deoxyglucose; Diet; Energy Metabolism; Enzymes; Equilibrium; Event; Fasting; Fatty acid glycerol esters; Focal Seizure; Glucose; Glutamates; Glutamine; Glycolysis; Heart Arrest; Hippocampus (Brain); Homeostasis; Hydroxybutyrates; Hyperglycemia; Impairment; Induced Heart Arrest; Intractable Epilepsy; Ketone Bodies; Ketones; Ketoses; Ketosis; Measures; Medical; Metabolic; Metabolism; Modeling; Nerve Degeneration; Nervous System Physiology; Neuraxis; Neurodegenerative Disorders; Neurons; Organ; Outcome; Oxidation-Reduction; Oxidative Stress; Parkinson Disease; Pathology; Phosphocreatine; Positron-Emission Tomography; Property; Pyruvate; Pyruvate Dehydrogenase Complex; Pyruvates; Rattus; Recovery; Regulation; Research Personnel; Resuscitation; Seizures; Signaling Molecule; Source; Staging; Staining method; Stains; Starvation; Stroke; Testing; Tissues; Tracer; Work; base; brain metabolism; energy balance; enzyme activity; experience; feeding; glucose metabolism; glucose transport; hexokinase; imaging modality; improved; in vivo; interest; ketogenic diet; neuropathology; neuroprotection; preconditioning; prevent; public health relevance; response; stroke recovery; therapy development; translational study; treatment strategy; uptake

DESCRIPTION (provided by applicant): The uptake and metabolism of ketone bodies in brain have been of interest to researchers and clinicians for decades but how they affect the coupling of blood flow and glucose metabolism, especially during chronic ketotic conditions, remains unclear. Although glucose is considered the primary fuel for brain, ketones supplement brain metabolism, especially under conditions of glucose sparing, such as fasting, starvation or high fat-low carbohydrate diet. The enzymes for ketone metabolism and the monocarboxylate transporters at the blood brain barrier are known to increase with fasting or ketogenic diet. It is known that cerebral ischemia, such as stroke (induced by cardiac arrest and resuscitation), results in altered glucose metabolism, the reduction of intracellular energy metabolites such as ATP, ADP and phosphocreatine and the accumulation of metabolic intermediates, such as lactate and adenosine. Degree of recovery of neurologic function following stroke (oxidative stress) is limited by the ability of the central nervous system to recover from an ischemic event. Based on our experiences we have developed the working hypothesis that ketones are effective against pathology associated with oxidative stress and/or altered glucose metabolism. The rationale is ketosis stabilizes glucose metabolism through the normalization of redox (lactate/pyruvate ratio) in brain. One potential mechanism is that ketone body metabolism differs from glucose such that when oxidized, acetyl-CoA units enter the Krebs-TCA cycle at the level of citrate bypassing glycolysis (the step after pyruvate dehydrogenase complex which is often a metabolic block following oxidative stress) and through feed-back regulation is known to down regulate glycolytic rates at the level of citrate, phosphofructokinase or hexokinase. Another proposed mechanism may be that ketosis facilitates anaplerosis (replenishment of the Krebs-TCA cycle intermediates) after oxidative challenges, a mechanism for neuroprotection. To investigate the effects of ketosis on cerebral metabolic rate for glucose (CMRglu) imaging modalities, such as PET analysis, and an in vivo rat model of ketosis will be used to determine if ketosis improves CMRglu and metabolic outcome following cardiac arrest and resuscitation. PUBLIC HEALTH RELEVANCE: Fasting, prolonged starvation or consumption of high fat-low carbohydrate diet (ketogenic diet) is known to result in ketosis and has been used for the treatment of intractable epilepsy, especially where the seizures are caused by insufficient glucose transport into the brain. Based on animal studies, ketosis has been suggested to possess neuroprotective properties against neurodegenerative diseases such as Alzheimer's, Parkinson's and recovery from focal stroke. However, there has been little progress in developing therapies that optimize ketosis as an approach to the medical treatment of neurodegenerative diseases, and, therefore, we would like to investigate the effects of ketosis on brain metabolism of glucose (CMRglu) using image (PET) analysis in ketotic rat and to determine if there is improved outcome following cardiac arrest and resuscitation.

描述（由申请人提供）：几十年来，研究人员和临床医生一直对大脑中酮体的摄取和代谢感兴趣，但它们如何影响血流和葡萄糖代谢的耦合，特别是在慢性酮症条件下，仍不清楚。虽然葡萄糖被认为是大脑的主要燃料，但酮可以补充大脑的新陈代谢，特别是在葡萄糖不足的情况下，例如禁食、饥饿或高脂肪低碳水化合物饮食。已知酮代谢酶和血脑屏障处的单羧酸转运蛋白会随着禁食或生酮饮食而增加。众所周知，脑缺血，如中风（由心脏骤停和复苏引起），会导致葡萄糖代谢改变，细胞内能量代谢物（如 ATP、ADP 和磷酸肌酸）减少，以及代谢中间体（如乳酸和腺苷）积累。中风（氧化应激）后神经功能的恢复程度受到中枢神经系统从缺血事件中恢复的能力的限制。根据我们的经验，我们提出了一个工作假设，即酮可以有效对抗与氧化应激和/或葡萄糖代谢改变相关的病理。其基本原理是酮症通过大脑中氧化还原（乳酸/丙酮酸比率）的正常化来稳定葡萄糖代谢。一种潜在的机制是酮体代谢与葡萄糖不同，因此当氧化时，乙酰辅酶A单位以柠檬酸水平进入克雷布斯-TCA循环，绕过糖酵解（丙酮酸脱氢酶复合物之后的步骤，通常是氧化应激后的代谢障碍）已知通过反馈调节可以下调柠檬酸、磷酸果糖激酶或己糖激酶水平的糖酵解速率。另一个提出的机制可能是酮症在氧化挑战后促进回补（Krebs-TCA 循环中间体的补充），这是一种神经保护机制。为了研究酮症对大脑葡萄糖代谢率 (CMRglu) 的影响，将使用 PET 分析等成像方式和体内酮症大鼠模型来确定酮症是否改善心脏骤停和复苏后的 CMRglu 和代谢结果。公共卫生相关性：已知禁食、长期饥饿或食用高脂低碳水化合物饮食（生酮饮食）会导致酮症，并已用于治疗顽固性癫痫，特别是由于葡萄糖转运至体内不足而引起癫痫发作的情况。脑。根据动物研究，酮症被认为具有神经保护特性，可预防阿尔茨海默病、帕金森病和局灶性中风等神经退行性疾病。然而，在开发优化酮症作为神经退行性疾病医学治疗方法的疗法方面进展甚微，因此，我们希望使用图像 (PET) 研究酮症对大脑葡萄糖代谢 (CMRglu) 的影响对酮症大鼠进行分析，以确定心脏骤停和复苏后的结果是否有所改善。