PROTECTION OF CNS CELLS FROM ISCHEMIA

保护中枢神经系统细胞免受缺血

• 批准号: 3411172
• 负责人: ADELBERT III AMES
• 金额: $ 13.34万
• 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/3411172
• 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).

这项研究的目的是探索如何保护 严重灌流不足的中枢神经系统细胞的活性。三 将采用以下方法：(1)减少能源需求 对细胞的保护；(2)对缺血毒性产物的保护； (3)纠正必要的缺血所致的缺陷 代谢物。大部分注意力将集中在第一个方面；因为 有很好的证据表明，大多数能量通常 由中枢神经系统细胞使用，用于代谢过程，使功能减退 而这些并不是生存所必需的，而且因为其中许多 进程可以被可逆地阻止。 实验将在体外进行，使用的是兔的视网膜 以中枢神经系统灰质为例，使用光诱发的 从视神经残端记录的电反应为 对三个层次持续生存能力的主要检验 构成视网膜回路的神经元。视网膜将会 在微型心肺装置中进行研究，该装置提供了 02消耗量、酸产量的在线测量(因此 糖酵解)，以及光诱发的电反应。在首字母中 对33种药物进行筛选，发现10种药物对可逆性有效 减少能源使用量；这些减少的能源使用量的组合 控制在50%以下，并且(在初步试验中) 提供保护以抵御缺血性的侮辱。 拟议的实验将寻求：识别代理人，以及 药剂组合，以减少能源需求；评估 这提供了对标准化的缺血侮辱的保护； 评估方案提供的保护以减少毒性影响 缺血(如钙离子、白三烯和前列腺素， 兴奋性毒性氨基酸、氧自由基)或评估 补充代谢中间体(例如，核苷、 核糖、谷氨酰胺、谷胱甘肽)。