PROTECTION OF CNS CELLS FROM ISCHEMIA

保护中枢神经系统细胞免受缺血

• 批准号: 3411173
• 负责人: ADELBERT III AMES
• 金额: $ 14.88万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 1991-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3411173
• 关键词: bioenergetics; brain disorder chemotherapy; brain metabolism; cell death; cerebral ischemia /hypoxia; evoked potentials; glutamine; glutathione; glycolysis; laboratory rabbit; neurochemistry; nucleosides; oxygen consumption; retina; ribose

The purpose of this research is to explore ways to preserve the viability of CNS cells that are being severely hypoperfused. Three approaches will be used: (1) reduction of the energy requirements of the cells; (2) protection against toxic products of ischemia; (3) correction of ischemia-induced deficiencies in essential metabolites. Most attention will be devoted to the first; because there is good evidence that the majority of the energy normally used by CNS cells is for metabolic processes that subserve function and that are not essential to viability, and because many of these processes can be reversibly blocked. The experiments will be performed in vitro, using the rabbit retina as an example of CNS gray matter and using the light-evoked electrical response recorded from the optic nerve stump as the principal test of the continued viability of the 3 layers of neurons that constitute the retinal circuits. The retinas will be studied in a miniature heart-lung apparatus which provides on- line measurements of 02 consumption, acid production (hence glycolysis), and light-evoked electrical responses. In an initial screening of 33 agents, 10 were found to be effective in reversibly reducing energy usage; combinations of these reduced energy usage to less than 50% of control, and (in a preliminary experiment) provided protection against an ischemic insult. The proposed experiments will seek to: identify agents, and combinations of agents, to reduce energy requirements; assess the protection this provides against a standardized ischemic insult; assess the protection provided by regimens to reduce toxic effects of ischemia (e.g., Ca++, leukotrienes and prostaglandins, excitotoxic amino acids, oxygen free radicals) or assess the effects of resupplying metabolic intermediates (e.g., nucleosides, ribose, glutamine, glutathione).

本研究的目的是探讨如何保护 严重低灌注的CNS细胞的活力。 三 将采用以下方法：（1）减少能源需求 （2）对缺血毒性产物的保护作用; (3)纠正缺血引起的基本 代谢物。 大多数注意力将集中在第一个方面，因为 有充分的证据表明，大部分的能量通常 中枢神经系统细胞使用的是代谢过程， 而这些对生存能力并不重要，因为其中许多 过程可以被可逆地阻断。 实验将在体外进行，使用兔视网膜 以中枢神经系统灰质为例， 从视神经残端记录的电反应为 3层持续生存能力的主要测试 构成视网膜回路的神经元。 视网膜会 在微型心肺设备中进行研究，该设备提供- O2消耗、酸生产（因此 糖酵解）和光诱发的电反应。 在初始 筛选了33种药物，发现10种药物对可逆性 减少能源使用;这些减少能源使用的组合 至低于对照的50%，并且（在初步实验中） 提供了针对缺血性损伤的保护。 拟议的实验将寻求：确定代理人， 结合剂，以减少能源需求;评估 这提供了针对标准化缺血性损伤的保护; 评估方案提供的保护，以减少毒性作用 局部缺血（例如，Ca++、白三烯和白藜芦醇， 兴奋性毒性氨基酸，氧自由基）或评估 再供应代谢中间体的影响（例如，核苷， 核糖、谷氨酰胺、谷胱甘肽）。