Oxaloacetate's Brain Effects

描述（由申请人提供）：增强脑线粒体呼吸可能对脑电子传递链酶活性降低的疾病有益。这包括几种常见疾病，如阿尔茨海默病和帕金森病。我们和其他人提出，将细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，这可能具有治疗效果。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（OAA）的还原为苹果酸盐与NADH氧化成NAD+相结合，具有特别的前景。OAA是一种二羧酸，是克雷布斯循环和糖异生的中间体。你可以购买它作为营养补充品。一家制造商将其作为热量限制模拟产品和“长寿补品”销售。这些说法是基于2009年的一项研究，在该研究中，经oaa处理的秀丽隐杆线虫比未经处理的线虫寿命更长。还报道了两项体内OAA脊椎动物的研究。第一个是1968年对人类糖尿病患者的研究，该研究发现OAA治疗降低了血糖水平。第二项是2003年对小鼠进行的一项研究，该研究发现OAA可以防止kainic酸引起的癫痫发作、大脑mtDNA降解和脂质过氧化。除了这三项研究外，补充OAA的效果基本上是未知的。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显著增加线粒体耗氧量。在小鼠中，我们发现系统给药OAA增加了脑PGC1a水平。另一方面，脑TNFa表达降低，ERK1/2磷酸化趋势相同。因此，基于概念和初步数据考虑，OAA作为一种促呼吸、促线粒体生物发生剂，可能作为一种穿透大脑的热量限制模拟物，值得进一步考虑。因此，我假设系统给予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给予OAA如何影响脑线粒体生物发生，线粒体生物发生中涉及的蛋白质和途径，以及OAA治疗小鼠的营养感知途径。在目的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途径。在Aim 2中，我们将描述老年小鼠在12个月的时间内接受OAA治疗的脑生物能量学和生物能量学相关途径。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OAA或类似OAA的药物来治疗大脑生物能量减少的疾病的案例将得到极大的加强。

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.