Oxaloacetate's Brain Effects

草酰乙酸对大脑的影响

基本信息

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
项目类别：
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&apos 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

项目摘要

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）：增强脑线粒体呼吸可能会通过减少的脑电子传输链酶活性使疾病受益。这包括几种常见疾病，例如阿尔茨海默氏病和帕金森氏病。我们和其他人提出，将细胞胞质氧化还原平衡转移到更氧化的状态可能会增加线粒体呼吸，这可能会带来治疗后果。为了完成这种操作，我的实验室已经筛选了许多化合物，初步实验表明草乙酸（OAA）的减少到苹果酸盐与NADH氧化为NAD+的氧化具有特殊的希望。 OAA是一种二羧酸，是克雷布斯循环和糖异生中间体。您可以将其作为营养补品购买。一家制造商将其推销为热量限制模仿和“寿命补充”。这些主张是基于2009年的一项研究，在该研究中，OAA处理的秀丽隐杆线虫蠕虫未经处理的蠕虫。还报道了两项体内OAA脊椎动物研究。第一个是1968年的人类糖尿病患者研究，发现OAA治疗降低了血糖水平。第二项是对小鼠进行的2003年研究，该研究发现OAA可防止海藻酸诱导的癫痫发作，脑mtDNA降解和脂质过氧化。除了这三项研究外，OAA补充效应本质上是未知的。在初步研究中，我们发现将OAA添加到神经母细胞瘤细胞中，可强烈增加线粒体氧的消耗。在小鼠中，我们发现系统施用的OAA增加了脑PGC1A水平。另一方面，脑TNFA表达降低，ERK1/2磷酸化沿相同方向趋势。因此，基于概念和初步数据注意事项OAA需要进一步的考虑作为促呼气的，促肌肉的生物发生剂，可能充当大脑渗透热量限制的模拟物。因此，我假设系统地施用的OAA将激活有助于或介导脑线粒体生物发生的途径。对这一假设的支持将证明有关OAA补充剂如何影响脑代谢，信号通路和基因表达的其他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施用的OAA如何影响与线粒体生物发生有关的脑部线粒体生物发生，蛋白质和途径以及OAA处理的小鼠中的营养感应途径。在AIM 1中，我们将表征大脑生物能学和与年轻OAA治疗的小鼠相关的途径。在AIM 2中，我们将在12个月内用OAA治疗的老年小鼠中脑生物能学和与生物能相关的途径。如果我现在提出的研究确认并扩展了我们的初步发现，则开发OAA或OAA样药物来治疗脑生物能量降低的疾病的情况将得到极大的增强。