NEUROPROTECTIVE EFFECTS OF KETONE BODY OXIDATION IN CEREBRAL ISCHEMIA

酮体氧化对脑缺血的神经保护作用

• 批准号: 8770382
• 负责人: KWEE LIU LIN THIO
• 金额: $ 22.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770382
• 关键词: Abbreviations; Acetoacetates; Acetyl Coenzyme A; Acetyl-CoA C-Acetyltransferase; Acids; Acute; Adult; Affect; Animal Model; Apoptotic; Astrocytes; Behavioral Assay; Biochemical; Biological Assay; Brain; Brain Injuries; Brain Ischemia; Carbohydrates; Cause of Death; Cell Death; Cell membrane; Cerebral Ischemia; Chloride Ion; Chlorides; Citrate (si)-Synthase; Citric Acid Cycle; Coenzyme A; Coenzyme A-Transferases; Enzymes; Equilibrium; Event; Exhibits; Failure; Fatty Acids; Fatty acid glycerol esters; Glutamates; Hydroxybutyrates; Interruption; Intervention; Ischemia; Ischemic Brain Injury; Ischemic Stroke; Ketone Bodies; Ketoses; Ketosis; Knockout Mice; Lead; Liver; Measurement; Metabolic; Metabolism; Middle Cerebral Artery Occlusion; Mitochondria; Modeling; Morbidity - disease rate; Mus; Necrosis; Neurons; Nicotinamide adenine dinucleotide; Nonesterified Fatty Acids; Nuclear Magnetic Resonance; Oxidoreductase; Phospholipids; Property; Reaction; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Research; Role; Source; Stroke; Testing; Thrombectomy; Vascular blood supply; acetoacetyl CoA; brain tissue; disability; experience; fatty acid oxidation; high risk; ketogenic diet; malic enzyme; mortality; neuroprotection; oxidation; public health relevance; quantum; response; small molecule; succinyl-coenzyme A; thrombolysis; triphenyltetrazolium

DESCRIPTION (provided by applicant): Stroke is a leading cause of morbidity and mortality in the US despite the availability of therapies such thrombolysis and thrombectomy. Focal ischemic stroke occurs when the blood supply to a portion of the brain is interrupted. The affected brain tissue experiences energy failure that can cause cell death. When the interruption is temporary, the ischemia reperfusion sequence initiates a cascade of events causing necrotic and apoptotic cell death. The metabolic response of the brain to energy failure is not completely understood, though one component of this response is a massive release of free fatty acids from plasma membrane phospholipids. Oxidation of these free fatty acids could produce ketone bodies. This project tests the hypothesis that locally produced ketone bodies within the brain are neuroprotective. This hypothesis extends the observation that ketone bodies administered exogenously or synthesized by the liver while on a ketogenic diet protect the brain from ischemic damage in animal models. Regardless of their source, whether neuroprotection from ischemia depends on ketone body oxidation is unknown. Ketone body oxidation requires the ketolytic enzyme (SCOT), which participates in the conversion of ketone bodies into acetyl CoA for entry into the tricarboxylic acid cycle. SCOT is present in neurons and astrocytes. Notably, astrocytes but not neurons oxidize fatty acids, and the synthesis of ketone bodies by astrocytes likely depends on SCOT. A role for SCOT in ketone body oxidation and synthesis is possible because the reaction it catalyzes is near equilibrium. The hypothesis that locally synthesized ketone bodies are neuroprotective during focal ischemia requires an astrocyte-neuron ketone body shuttle. Accordingly, astrocytes would oxidize fatty acids and need SCOT to synthesize ketone bodies. The astrocytes would then send the ketone bodies to neurons, which then oxidize them in a SCOT dependent manner. This model provides a framework to test the hypothesis that ketone bodies protect the brain from ischemia / reperfusion damage via a mechanism requiring their oxidation. This project will test this hypothesis by examining the effects of transient proximal middle cerebral artery occlusion (tMCAO) in neuron-specific and astrocyte-specific SCOT knockout mice using histological, biochemical, and behavioral assays.

描述（由申请方提供）：尽管存在溶栓和血栓切除术等治疗方法，但卒中仍是美国发病率和死亡率的主要原因。局部缺血性中风发生时，血液供应到大脑的一部分被中断。受影响的脑组织经历能量衰竭，可能导致细胞死亡。当中断是暂时的时，缺血再灌注序列启动引起坏死和凋亡细胞死亡的级联事件。大脑对能量衰竭的代谢反应还不完全清楚，尽管这种反应的一个组成部分是从质膜磷脂中大量释放游离脂肪酸。这些游离脂肪酸的氧化可产生酮体。该项目测试了大脑中局部产生的酮体具有神经保护作用的假设。这一假设扩展了在动物模型中外源性给予或在生酮饮食中由肝脏合成的酮体保护脑免受缺血性损伤的观察结果。无论其来源如何，缺血的神经保护是否依赖于酮体氧化尚不清楚。酮体氧化需要溶酮酶（SCOT），其参与酮体转化为乙酰辅酶A，以进入三羧酸循环。SCOT存在于神经元和星形胶质细胞中。值得注意的是，星形胶质细胞而不是神经元氧化脂肪酸，并且星形胶质细胞的酮体合成可能依赖于SCOT。SCOT在酮体氧化和合成中的作用是可能的，因为它催化的反应接近平衡。局部合成的酮体在局灶性缺血期间具有神经保护作用的假设需要星形胶质细胞-神经元酮体穿梭。因此，星形胶质细胞会氧化脂肪酸并需要SCOT来合成酮体。然后星形胶质细胞将酮体发送给神经元，然后神经元以SCOT依赖的方式氧化它们。该模型提供了一个框架，以检验酮体通过需要其氧化的机制保护脑免受缺血/再灌注损伤的假设。本项目将通过使用组织学、生物化学和行为学分析来检查短暂近端大脑中动脉闭塞（tMCAO）对神经元特异性和星形胶质细胞特异性SCOT敲除小鼠的影响来验证这一假设。