HYDROGEN IONS AND BRAIN INFARCTION

氢离子与脑梗塞

• 批准号: 3399119
• 负责人: Richard P Kraig
• 金额: $ 14.27万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1991-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3399119
• 关键词: acid base balance; acidity /alkalinity; acidosis; blood brain barrier; brain edema; brain metabolism; calcium metabolism; cerebral ischemia /hypoxia; chronic brain damage; disease /disorder model; electroencephalography; glia; hippocampus; histology; homeostasis; laboratory rat; membrane activity; membrane proteins; membrane structure; microelectrodes; microscopy; neurons; neurophysiology; pyramidal cells; synapses

The pathogenesis of ischemic brain injury remains poorly understood. Brain lactate content is directly proportional to the severity of ischemic brain damage after complete ischemia and implies that acidosis can irreversibly injure brain. However, the molecular mechanisms of the H+ induced injury remain incompletely understood. Our studies suggest that under ischemic conditions which can evolve to infarction, the generation of excess H+ remains confined to a brain space consistent with glia. Such compartmentalization for H+ may be a result of altered properties of glial cell membranes. The contribution of brain cell membranes to H+ homeostasis during ischemia has not been emphasized. A hypothesis is developed based on in vivo recordings that brain infarction from ischemia occurs because of severe acidosis greater than 5.2 pH in glia. Furthermore, this acidosis is likely to result from continued glial lactic acid production coupled to loss of intracellular bicarbonate stores and failure of plasma membrane antiport systems for H+ transport but retained plasma membrane integrity. We plan to examine H+ homeostasis in mammalian neurons, glia, and their interstitial microenvironment. Pairs of H+ selective microelectrodes will be used to simultaneously monitor interstitial and selected intracellular (H+) as well as cell membrane electrical characteristics under ischemic conditions. H+ in ischemia may, in addition to a direct toxic effect, injure brain indirectly through increased modality, loss of cell volume regulation, and resultant postischemic lethal brain edema. Therefore, we will also correlate changes in brain H+ homeostasis to these latter variables of tissue modality, lactate content, and per cent swelling. Cell injury will be assessed by changes in cell electrical characteristics, trans-membrane ion gradients, and visualized by light microscopic techniques. Cells will be identified by their evoked membrane electrical characteristics and through selected horse radish peroxidase staining. The general objective of this study is to characterize the patterns and mechanisms of H+ regulation in mammalian brain cells and their interstitial microenvironment under normal and ischemic conditions so as to test the hypothesis that inhibition of plasma membrane H+ regulatory mechanisms can lead to irreversible dysfunction of glial cells and subsequent brain infarction.

缺血性脑损伤的发病机理仍然了解不足。 脑 乳酸含量与缺血性大脑的严重程度成正比 彻底缺血后损坏，并暗示酸中毒可以不可逆转地 伤害大脑。 但是，H+诱导损伤的分子机制 保持不完全理解。 我们的研究表明，可以发展为 梗塞，多余的H+的产生仍然局限于大脑空间 与神经胶质一致。 H+的这种隔室化可能是 神经胶质细胞膜的特性改变。 脑细胞的贡献 尚未强调缺血期间H+稳态的膜。 一个 假设是基于体内记录的大脑梗塞的。 由于严重的酸中毒大于5.2 pH，从缺血发生。 神经胶质。 此外，这种酸中毒很可能是由持续神经胶质引起的 乳酸产生与细胞内碳酸氢盐储存的损失相结合 H+传输的质膜隔膜系统的失败，但 保留质膜完整性。 我们计划检查哺乳动物神经元，神经胶质的H+稳态及其 间质微环境。 成对的H+选择性微电极将 用于同时监测间隙和选定的细胞内 （H+）以及缺血下的细胞膜电特性 状况。 H+缺血可能，除了直接有毒作用外， 通过增加的方式，细胞体积损失间接伤害大脑 调节和导致的缺血后致死性脑水肿。 因此，我们 还将将脑H+稳态的变化与后者相关联 组织方式，乳酸含量和肿胀的变量。 细胞 受伤将通过细胞电特征的变化评估， 跨膜离子梯度，并通过光显微镜进行可视化 技术。 细胞将通过其诱发的膜电鉴定 特征和通过选定的马萝卜过氧化物酶染色。 这项研究的一般目标是表征模式和 哺乳动物脑细胞中H+调节的机制 在正常和缺血状态下的微环境，以测试 假设抑制质膜H+调节机制可以 导致神经胶质细胞和随后的大脑的不可逆转功能障碍 梗塞。