INTRACELLULAR CATIONS AND EXCITOTOXICITY

描述：（改编自申请人的摘要）：广泛理解的是， 谷氨酸触发的急性神经元损伤依赖于钙进入 神经元和损伤的最快速形式是由激活介导的， N-甲基-D-天冬氨酸受体。然而，在以前的研究中， 在神经元损伤的体外模型中， NMDA受体激活的神经毒性作用的特异性，因为 区分有毒和无毒细胞内钙离子的困难 变化在重新评估将钙变化与神经元 显然，有必要重新考虑这些问题。 与损伤相关的钙变化幅度，因为先前 研究可能没有提供准确的结果。此外，不受重视的 通常使用的荧光染料的选择性问题， 细胞内二价阳离子表明镁和锌也应该 被认为是兴奋性毒性损伤的候选神经毒素。 这些研究的长期目标是了解离子机制， 谷氨酸会杀死神经元申请人计划：确定非NMDA 受体激动剂诱导急性神经元损伤， 他们的变化是增加;确定是否的大小， 谷氨酸盐刺激神经元细胞内镁的变化， 这改变了线粒体功能;决定了细胞内 锌的变化以及它们如何与神经元损伤相关;以及，确定 保护神经元免受锌介导的损伤。有许多 各种阳离子介导的 伤害的形式，并提出的方法是调查这些 关系，而且，还利用方法上的相似之处， 适于测量感兴趣的每个离子。

DESCRIPTION: (Adapted from applicant's abstract): It is widely appreciated that glutamate-triggered acute neuronal injury is dependent on calcium entry into neurons and that the most rapid form of injury is mediated by the activation of N-methyl-D-aspartate receptors. However, in previous studies that have used in vitro models of neuronal injury it has been difficult to account for the specificity of the neurotoxic effects of NMDA receptor activation because of the difficulty in distinguishing toxic and non-toxic intracellular calcium changes. In re-evaluating the studies that link calcium changes to neuronal injury it becomes apparent that it is necessary to reconsider the issues of the magnitude of calcium changes that are associated with injury because previous studies may not have provided accurate results. In addition, unappreciated issues of the selectivity of the commonly used fluorescent dyes for intracellular divalent cations suggest that magnesium and zinc should also be considered as candidate neurotoxins in excitotoxic injury. The long-term goal of these studies is to understand the ionic mechanisms by which glutamate kills neurons. The applicants plan to: determine if non-NMDA receptor agonists induce acute neuronal injury if the magnitude of the calcium change they induce is increased; determine if the magnitude of the intracellular Mg change in neurons is stimulated by glutamate, and how would this alter mitochondrial function; determine the magnitude of intracellular zinc changes and how they may relate to neuronal injury; and, to determine the mechanisms neurons are protected from zinc-mediated injury. There are a number of potentially important interrelationships between the various cation-mediated forms of injury, and the proposed approach is to investigate these relationships, and, also to exploit the similarities in methodology that can be adapted to measure each ion of interest.