Oxaloacetate's Brain Effects

草酰乙酸对大脑的影响

• 批准号: 8418687
• 负责人: RUSSELL H. SWERDLOW
• 金额: $ 7.29万
• 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/8418687
• 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.

描述(由申请人提供)：增强大脑线粒体呼吸可以使大脑电子传递链酶活性降低的疾病受益。这包括几种常见的疾病，如阿尔茨海默氏症和帕金森氏症。我们和其他人提出，将细胞胞浆氧化还原平衡转移到更氧化的状态可能会增加线粒体的呼吸，这可能会产生治疗效果。为了完成这一操作，我的实验室筛选了许多化合物，初步实验表明草酰乙酸酯(OAA)具有特别的前景，它的还原为苹果酸与NADH氧化为NAD+相结合。OAA是一种二元酸，是Krebs循环和糖异生的中间产物。你可以买它作为营养补充剂。一家制造商将其作为一种模拟卡路里限制和“长寿补充剂”进行销售。这些说法是基于2009年的一项研究，在该研究中，经过OAA处理的线虫比未经处理的线虫存活时间更长。两个活体OAA脊椎动物的研究也被报道。第一个是1968年对人类糖尿病患者的研究，发现OAA治疗降低了血糖水平。第二项是2003年在小鼠身上进行的一项研究，该研究发现OAA可以预防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，补充高龄津贴的效果基本上是未知的。在初步研究中，我们发现在神经母细胞瘤细胞中加入OAA可以显著增加线粒体的耗氧量。在小鼠身上，我们发现系统服用OAA会增加大脑中PGC1a的水平。另一方面，脑内TNFa表达降低，ERK1/2磷酸化趋势相同。因此，基于概念性的和初步的数据考虑，OAA值得进一步考虑作为一种促进呼吸的、有利于线粒体的生物发生剂，可能作为一种脑穿透性热量限制模拟物。因此，我假设系统管理的OAA将激活有助于或介导脑线粒体生物发生的途径。支持这一假设将证明补充高龄津贴如何影响大脑新陈代谢、信号通路和基因表达的更多、更详细的研究是合理的。我们现在提出的试点研究将进一步测试系统地给予OAA如何影响脑线粒体生物发生、与线粒体生物发生有关的蛋白质和途径，以及OAA处理的小鼠的营养感知途径。在目标1中，我们将描述OAA处理的年轻小鼠的脑生物能量学和生物能量学相关的途径。在目标2中，我们将在12个月的时间里描述OAA治疗的老年小鼠的脑生物能量学和生物能量学相关的途径。如果我现在提出的研究证实并扩展了我们的初步发现，那么开发高龄津贴或类似高龄津贴的药物来治疗大脑生物能量降低的疾病的理由将大大增强。