HYDROGEN IONS AND BRAIN INFARCTION

氢离子与脑梗塞

• 批准号: 3399118
• 负责人: Richard P Kraig
• 金额: $ 6.16万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 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 1988-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3399118
• 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; membrane activity; 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制尚不清楚。脑区 乳酸含量与脑缺血的严重程度成正比 完全缺血后的损害，并暗示酸中毒可以不可逆转 伤及脑部。然而，H+诱导损伤的分子机制 仍然没有完全被理解。 我们的研究表明，在缺血条件下，可能演变为 脑梗塞，过量H+的产生仍局限于大脑空间 与神经胶质细胞一致。H+的这种划分可能是由于 改变了神经胶质细胞膜的性质。脑细胞的贡献 膜在缺血时对H+动态平衡的作用尚未得到重视。一个 假说是基于脑梗塞的活体记录而提出的 由于严重的酸中毒超过5.2PH值而发生的缺血 神经胶质细胞。此外，这种酸中毒很可能是由于持续的神经胶质细胞引起的。 乳酸生产与胞内碳酸氢盐储存的损失有关 以及H+转运的质膜反向转运系统的故障 保持质膜的完整性。 我们计划研究哺乳动物神经元、神经胶质细胞和它们的H+稳态 间隙微环境。成对的H+选择性微电极将 用于同时监测间质和选定的细胞内 (H+)以及细胞膜在缺血状态下的电特性 条件。缺血中的H+除了直接的毒性作用外，还可能 通过增加形态、细胞体积损失间接损伤大脑 调节，以及由此导致的脑缺血后致死性脑水肿。因此，我们 也会将大脑H+动态平衡的变化与后者联系起来 组织形态、乳酸含量和肿胀百分比的变量。细胞 损伤将通过细胞电特性的变化来评估， 跨膜离子梯度，并用光学显微镜可视化 技巧。细胞将通过它们被激发的膜电信号来识别 并通过精选的马萝卜过氧化物酶染色鉴定。 这项研究的总体目标是描述这些模式和 哺乳动物脑细胞及其间质的H~+调节机制 正常和缺血条件下的微环境，以测试 假设质膜H+调节机制的抑制可以 导致不可逆的胶质细胞功能障碍和随后的脑功能障碍 脑梗塞。