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有益于脑电子传递链酶活性降低的疾病。这包括几种常见疾病，例如阿尔茨海默病和帕金森病。我们和其他人提出，将细胞胞质氧化还原平衡转向更氧化的状态可能会增加线粒体呼吸，这可能会产生治疗效果。为了完成这一操作，我的实验室筛选了多种化合物，初步实验表明草酰乙酸 (OAA) 具有特别的前景，其还原为苹果酸并与 NADH 氧化为 NAD+ 相结合。 OAA 是一种二羧酸，是克雷布斯循环和糖异生中间体。您可以购买它作为营养补充剂。一家制造商将其作为热量限制模拟物和“长寿补充剂”进行营销。这些说法基于 2009 年的一项研究，其中经过 OAA 处理的线虫比未经处理的线虫寿命更长。还报道了两项 OAA 脊椎动物体内研究。第一个是 1968 年针对人类糖尿病患者的一项研究，该研究发现 OAA 治疗可以降低血糖水平。第二项是 2003 年对小鼠进行的一项研究，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，OAA 补充剂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 会显着增加线粒体耗氧量。在小鼠中，我们发现全身施用 OAA 会增加大脑 PGC1a 水平。另一方面，脑 TNFa 表达减少，ERK1/2 磷酸化呈相同方向发展。因此，基于概念和初步数据考虑，OAA 值得进一步考虑作为一种促呼吸、促线粒体生物发生剂，可以充当大脑穿透性热量限制模拟物。因此，我假设全身施用 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对 OAA 补充剂如何影响大脑代谢、信号通路和基因表达进行更多、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施用 OAA 如何影响 OAA 治疗小鼠的脑线粒体生物发生、与线粒体生物发生有关的蛋白质和途径以及营养感应途径。在目标 1 中，我们将描述经 OAA 治疗的年轻小鼠的大脑生物能学和生物能学相关通路。在目标 2 中，我们将描述接受 OAA 治疗 12 个月的老年小鼠的大脑生物能学和生物能学相关通路。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 类药物来治疗大脑生物能降低的疾病的理由将得到极大加强。