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.

这项研究的总体目标是调查 高能量的生化机制，使围产期的大脑受损 以及如何预防或减少脑损伤 通过特定的治疗方式。 具体目标包括：（1） 确定高度变化程度之间的关系 能量代谢产物（ATP、PCr）在缺氧缺血和神经病理过程中的作用 结果; 2）确定是否有特定的治疗 已知最终保存高能量代谢物的操作， 持续预防或减少缺氧缺血性脑损伤; 3） 改进NMR测量的空间定位， 反映了高能量代谢的离散区域的变化， 探讨Mg ~（++）、Mg ~（++）和Mg ~（++）的空间依赖性， 重要的辅因子在许多重要的酶的调节 反应，包括神经传递。 使胎儿缺氧- 缺血性脑损伤，出生后7天大鼠将经历单侧 颈总动脉结扎，然后用8%的氧气缺氧， 37摄氏度长达3小时;一种已知会产生选择性 大多数动物出现神经元坏死或梗死。 期间或 在缺氧缺血后，动物将经历这些程序， 为了获得连续的31 P和1H NMR光谱， 为了半定量地测量高能量 磷酸盐储备和乳酸盐。 以下 缺氧缺血，未成熟的大鼠将与它们的母体一起饲养， 出生后30天，他们将接受灌注- 固定他们的大脑进行神经病理学分析和评分， 脑损伤 额外的实验将包括温和的 低温（34或31摄氏度）或禁食保存高- 在缺氧缺血期间和之后的能量磷酸盐储备。 实验还将包括经历缺氧缺血的未成年大鼠 分别接受别嘌呤醇（100或200 mg/g/kg）、M-801（0.5- 100 mg/kg）、M-802（0.5- 100 mg/kg）和M-803（0.5- 100 mg/kg）。 10 mg/kg）、尼莫地平1-2 mg/kg）或MgS 〇 4（0.3-0.6 mg/kg）s.c.; 将经历脑缺氧-缺血的未治疗的同窝仔用作 对照 分析程序将包括连续测量 用31 P和1H NMR光谱以及脑组织分析， 高能磷酸盐储备（磷酸肌酸、ATP、ADP、AMP）， 使用高压液相色谱法或酶法测定乳酸盐， 荧光测定法 最后，将开发一种技术， 未成熟的特定区域内的NMR信号的空间定位 老鼠的大脑