Oxaloacetate's Brain Effects

草酰乙酸对大脑的影响

• 批准号: 8256105
• 负责人: RUSSELL H. SWERDLOW
• 金额: $ 7.55万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256105
• 关键词: Affect; Age; Alzheimer' s Disease; Bioenergetics; Biogenesis; Blood Glucose; Brain; CREB1 gene; Caenorhabditis elegans; Caloric Restriction; Cells; Citrate (si)-Synthase; Citrates; Citric Acid Cycle; Coupled; Data; Dicarboxylic Acids; Disease; Electron Transport; Equilibrium; FOXO1A gene; Future; Gene Expression; Gluconeogenesis; Glucose; Human; Insulin; Kainic Acid; Laboratories; Life Extension; Lipid Peroxidation; Longevity; MAP Kinase Gene; MAPK14 gene; MAPK3 gene; Malates; Manufacturer Name; Marketing; Mediating; Mitochondria; Mitochondrial DNA; Monitor; Mus; NADH; Neurodegenerative Disorders; Oxalacetic Acid; Oxaloacetates; Oxidation-Reduction; Oxygen Consumption; Parkinson Disease; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Pilot Projects; Proteins; Proto-Oncogene Proteins c-akt; Reaction; Reporting; Respiration; Route; Seizures; Signal Transduction; Signaling Pathway Gene; Supplementation; Testing; Therapeutic; Weight; aged; anti aging; base; brain metabolism; case finding; cytochrome c; detection of nutrient; diabetic; dietary supplements; enzyme activity; glucose tolerance; human FRAP1 protein; in vivo; interest; intraperitoneal; mimetics; neuroblastoma cell; oxidation; prevent; research study; trend

DESCRIPTION (provided by applicant): Enhancing brain mitochondrial respiration could conceivably benefit diseases with reduced brain electron transport chain enzyme activities. This includes several common diseases such as Alzheimer's disease and Parkinson's disease. We and others have proposed that shifting cell cytosolic redox balances towards a more oxidized state might increase mitochondrial respiration and that this may have therapeutic consequences. To accomplish this manipulation my laboratory has screened a number of compounds, and preliminary experiments suggest oxaloacetate (OAA), whose reduction to malate is coupled to the oxidation of NADH to NAD+, holds particular promise. OAA, a dicarboxylic acid, is a Krebs cycle and gluconeogenesis intermediate. You can purchase it as a nutritional supplement. One manufacturer markets it as a caloric restriction mimetic and "longevity supplement". These claims are based on a 2009 study in which OAA-treated C. elegans worms outlived untreated worms. Two in vivo OAA vertebrate studies are also reported. The first is a 1968 study of human diabetics, which found that OAA treatment lowered blood glucose levels. The second is a 2003 study performed on mice, which found OAA prevented kainic acid-induced seizures, brain mtDNA degradation, and lipid peroxidation. Aside from these three studies OAA supplementation effects are essentially unknown. In preliminary studies we found adding OAA to neuroblastoma cells robustly increased mitochondrial oxygen consumption. In mice, we found systemically administered OAA increased brain PGC1a levels. Brain TNFa expression, on the other hand, was reduced and ERK1/2 phosphorylation trended in the same direction. Based on conceptual and preliminary data considerations OAA therefore warrants further consideration as a pro-respiration, pro-mitochondrial biogenesis agent that may act as a brain-penetrating caloric restriction mimetic. I am therefore hypothesizing systemically administered OAA will activate pathways that contribute to or mediate brain mitochondrial biogenesis. Support for this hypothesis would justify additional, more detailed studies of how OAA supplements affect brain metabolism, signaling pathways, and gene expression. The pilot studies we now propose will further test how systemically administered OAA affects brain mitochondrial biogenesis, proteins and pathways that are implicated in mitochondrial biogenesis, and nutrient sensing pathways in OAA-treated mice. In Aim 1 we will characterize brain bioenergetics and bioenergetics-related pathways in young OAA-treated mice. In Aim 2 we will characterize brain bioenergetics and bioenergetics-related pathways in aged mice treated with OAA over a 12-month period. If the studies I now propose confirm and extend our preliminary findings, the case for developing OAA or OAA-like drugs for the treatment of diseases with reduced brain bioenergetics will be immensely strengthened. PUBLIC HEALTH RELEVANCE: We will test the ability of oxaloacetic acid (OAA) to activate brain mitochondrial biogenesis, proteins and pathways implicated in mitochondrial biogenesis, and nutrient sensing pathways in mice. Our hypothesis is that systemically administered OAA will activate pathways that contribute to or mediate brain mitochondrial biogenesis. Our preliminary data show OAA functions as a pro-respiration, pro-mitochondrial biogenesis agent that acts as a brain-penetrating caloric restriction mimetic; confirming and extending our preliminary data would support the case for developing OAA or OAA-like drugs for the treatment of diseases with reduced brain bioenergetic capacity.

描述（由申请人提供）：增强脑线粒体呼吸可能有益于脑电子传递链酶活性降低的疾病。这包括几种常见的疾病，如阿尔茨海默病和帕金森病。我们和其他人已经提出，将细胞胞质氧化还原平衡向更氧化的状态转移可能会增加线粒体呼吸，这可能具有治疗效果。为了完成这种操作，我的实验室筛选了许多化合物，初步实验表明草酰乙酸（OAA），其还原为苹果酸与NADH氧化为NAD+相结合，具有特别的前景。OAA是一种二羧酸，是克雷布斯循环和异源生成的中间体。您可以将其作为营养补充剂购买。一家制造商将其作为热量限制模拟物和“长寿补充剂”进行销售。这些说法是基于2009年的一项研究，其中OAA治疗的C。秀丽蠕虫比未处理的蠕虫活得更久。还报道了两项体内OAA脊椎动物研究。第一项是1968年对人类糖尿病患者的研究，该研究发现OAA治疗可以降低血糖水平。第二个是2003年对小鼠进行的研究，发现OAA可以防止红藻氨酸诱导的癫痫发作，大脑mtDNA降解和脂质过氧化。除了这三项研究之外，补充OAA的效果基本上是未知的。在初步研究中，我们发现向神经母细胞瘤细胞中添加OAA强烈增加了线粒体耗氧量。在小鼠中，我们发现全身给予OAA会增加大脑PGC 1a水平。另一方面，脑TNF α表达减少，ERK 1/2磷酸化趋势相同。基于概念和初步数据考虑，OAA因此值得进一步考虑作为促呼吸、促线粒体生物发生剂，其可充当脑穿透热量限制模拟物。因此，我假设全身给予OAA将激活有助于或介导脑线粒体生物合成的途径。支持这一假设将证明额外的，更详细的研究如何OAA补充剂影响大脑代谢，信号通路和基因表达。我们现在提出的试点研究将进一步测试全身给予OAA如何影响脑线粒体生物合成，与线粒体生物合成有关的蛋白质和途径，以及OAA治疗小鼠的营养感应途径。在目标1中，我们将描述年轻OAA处理小鼠的脑生物能量学和生物能量学相关通路。在目标2中，我们将描述在12个月的时间内用OAA治疗的老年小鼠的脑生物能量学和生物能量学相关通路。如果我现在提出的研究证实并扩展了我们的初步发现，那么开发OAA或OAA样药物来治疗大脑生物能量减少的疾病的情况将大大加强。 公共卫生关系：我们将测试草酰乙酸（OAA）激活小鼠脑线粒体生物合成、线粒体生物合成中涉及的蛋白质和途径以及营养感应途径的能力。我们的假设是，全身给予OAA将激活有助于或介导脑线粒体生物合成的途径。我们的初步数据显示OAA作为促呼吸、促线粒体生物发生剂起作用，其充当脑穿透热量限制模拟物;确认和扩展我们的初步数据将支持开发OAA或OAA样药物用于治疗脑生物能量能力降低的疾病的情况。