ENERGY METABOLISM

能量代谢

• 批准号: 6272281
• 负责人: MICHAEL B SMITH
• 金额: $ 12.04万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6272281
• 关键词: acidity /alkalinity; adenine nucleotides; adenosine triphosphate; allopurinol; beta hydroxybutyrate; bioenergetics; brain injury; brain metabolism; calcium channel blockers; cerebral ischemia /hypoxia; chemoprevention; creatine phosphate; divalent cations; dizocilpine; fasting; glycolysis; histopathology; hypothermia; immature animal; ketone body; laboratory rat; magnesium; neuroprotectants; nuclear magnetic resonance spectroscopy; perinatal

The overall objective of this research component is to investigate the high energy biochemical mechanisms whereby the perinatal brain is damaged by hypoxia-ischemia and how brain injury can be prevented or reduced through specific modalities of therapy. Specific aims include: 1) to ascertain the relationship between the extent of alterations in high energy metabolites (ATP,PCr) during hypoxia-ischemia and neuropathologic outcome; 2) to determine whether or not specific therapeutic manipulations known to preserve high energy metabolites ultimately and consistently prevent or reduce hypoxic-ischemic brain damage; 3) to improve the spatial localization of NMR measurements to more accurately reflect the changes of high energy metabolism in discrete region of the immature brain; 4) to explore the spatial dependence of Mg++, an important co-factor in the regulation of many essential enzymatic reactions, including neurotransmission. To produce perinatal hypoxic- ischemic brain damage, 7-day postnatal rats will undergo unilateral common carotid artery ligation followed by hypoxia with 8% oxygen at 37degreesC for up to 3 hours; an insult known to produce selective neuronal necrosis or infarction in the majority of animals. During or following hypoxia-ischemic, the animals will undergo those procedures necessary to obtain sequential 31P and 1H NMR spectra which will allow for a semi-quantitative measure of the alterations in high-energy phosphate reserves and lactate which result from the insult. Following hypoxia-ischemia, the immature rats will be reared with their dams until 30 days of postnatal age at which time they will undergo perfusion- fixation of their brains for neuropathologic analysis and scoring of brain damage. Additional experiments will include the effect of mild hypothermia (34 or 31degreesC) or of fasting on the preservation of high- energy phosphate reserves during and following hypoxia-ischemia. Experiments also will include immature rats undergoing hypoxia-ischemia which have received either allopurinol (100 or 200 md\g/kg), M-801 (0.5- 10 mg/kg), nimodipine )1-2 mg/kg), or MgS04 (0.3-0.6 mg/kg) s.c.; untreated littermates undergoing cerebral hypoxia-ischemia will serve as controls. Analytical procedures will include sequential measurements with 31P and 1H NMR spectroscopy as well as brain tissue analysis of high-energy phosphate reserves (phosphocreatine, ATP, ADP, AMP) and lactate using high pressure liquid chromatography or enzymatic, fluorometric methods. Finally, a technique will be developed to allow spatial localization of NMR signals within specific regions of immature rat brain.

该研究部分的总体目的是研究 高能生化机制，围产期大脑受损 通过缺氧 - 缺血以及如何预防或减少脑损伤 通过特定的治疗方式。 具体目的包括：1） 确定高改变程度之间的关系 缺氧 - 缺血和神经病理学期间能量代谢物（ATP，PCR） 结果; 2）确定是否具体治疗 已知可以保留高能代谢产物的操纵，并且 一贯预防或减少缺氧缺血性脑损伤； 3）到 改善NMR测量的空间定位到更准确的 反映高能代谢在离散区域的变化 未成熟的大脑； 4）探索Mg ++的空间依赖性 在许多基本酶法调节中的重要副因素 反应，包括神经传递。 产生围产期低氧 缺血性脑损伤，7天的产后大鼠将发生单侧 常见的颈动脉连接，然后是缺氧，氧气为8％ 37Degreesc最多3个小时；已知会产生选择性的侮辱 大多数动物的神经元坏死或梗塞。 期间 在缺氧 - 缺血性之后，动物将接受这些程序 获得顺序的31p和1H NMR光谱所需的必要 对于高能改变的半定量度量 磷酸盐储备和乳酸是由侮辱引起的。 下列的 缺氧 - 异常，未成熟的大鼠将饲养水坝直到 30天的产后年龄，他们将经历灌注 - 将其大脑固定进行神经病理学分析和评分 脑损伤。 其他实验将包括温和的效果 体温过低（34或31Degreesc）或在保存高 - 在缺氧 - 缺血性缺血期间和之后磷酸盐储量。 实验还将包括未成熟的大鼠患缺氧 - 异常 已经接受过素醇（100或200 MD \ g/kg），M-801（0.5-- 10 mg/kg），nimodipine）1-2 mg/kg）或mgs04（0.3-0.6 mg/kg）s.c。; 未经脑缺氧 - 异常的未经治疗的同窝室将作为 控件。 分析程序将包括顺序测量 具有31p和1H NMR光谱以及脑组织分析 高能磷酸盐储量（磷酸磷酸盐，ATP，ADP，AMP）和 使用高压液相色谱或酶促的乳酸， 荧光法。 最后，将开发一种技术以允许 NMR信号的空间定位在特定的未成熟区域内 大鼠大脑。