GLUTAMATE, EXCITOTOXINS AND NEURONAL-GLIAL INTERACTIONS

推测的氨基酸的功能或代谢异常 (Aa)神经递质谷氨酸(GLU)和GABA 与几种神经系统疾病的病因或后遗症有关 精神错乱。谷氨酸或谷氨酸类似物，例如海人酸兴奋性毒素 (KA)和QuisQualate(Quis)，当直接注射到中枢神经系统时 结构导致神经元死亡，增加了耐人寻味的可能性 内源性兴奋毒性活性可能参与了这种 精神错乱。研究表明，能量的变化 GLU的代谢和正常神经元-神经胶质代谢可能 在这种神经毒性中起作用。此应用程序是一个 继续这些努力。最近的研究表明，c1- 运输，可能通过C1-/HCO3-反向运输，可能起主要作用 在后遗症潜在的基本机制中的作用 兴奋性毒性。这项提案将重点放在使用c1- 转运抑制剂对兴奋性毒性诱导效应的影响 系统。将在大鼠脑小脑中测量C1-摄取 在含有刺激性毒素的情况下使用放射性Na36C1切片， 以及其他去极剂，如K+和藜芦碱。已知 在孵化过程中将添加C1转运的抑制剂，以查看 哪种类型的载体系统被处理激活。 雏鸡的胚胎视网膜也对 兴奋性毒性。毒性的发展方面将是 通过使用E6到E21岁的视网膜进行检查，这对应于 特定的发展阶段。结果将与 AA代谢的变化，无论是在动态方面 利用放射性前体进行测量，发展 酶的测定采用直接测定法和免疫组织化学方法。 组织切片中使用的各种氯离子转运抑制剂 将对研究进行研究，以确定哪些(如果有的话)可以预防 神经毒性。C1-/HCO3-系统也调节细胞内 某些细胞类型的pH值。细胞内的pH值将在 一种用兴奋性毒素治疗视网膜的方法 它利用了放射性苯甲酸。还将进行研究 用新生大鼠脑和胚胎雏鸡的胶质细胞培养 视网膜。刺激性毒素的直接作用，在存在和 将检查是否存在高水平的K+，包括 氯摄取的变化和细胞内pH的变化。这些 研究应该对假说给出肯定或否定的答案 关于兴奋性毒性后遗症的潜在机制和 神经胶质细胞的作用。更重要的是，它们可能会为 研究神经元和神经胶质细胞之间的相互作用。

Aberrations of function or metabolism of the putative amino acid (AA) neurotransmitters, glutmate (GLU) and GABA, have been implicated in the etiology or sequelae of several neurological disorders. GLU or GLU-analogs, e.g., the excitotoxins kainate (KA) and quisqualate (QUIS), when injected directly into CNS structures cause neuronal death, raising the intriguing possibility that endogenous excitotoxicity activity may be involved in such disorders. Studies have shown that an alteration in energy metabolism and normal neuronal-glial metabolism of GLU may play a role in this neurotoxicity. This application is a continuation of those efforts. Recent work has shown that C1- transport, perhaps via the C1-/HCO3- antiport, may play a major role in basic mechanisms underlying the sequelae of excitotoxicity. This proposal will focus on the use of C1- transport inhibitors on excitotoxicity-induced effects in our test systems. C1- uptake will be measured in rat brain cerebellar slices using radioactive Na36C1 in the presence of excitotoxins, and other depolarizing agents such as K+ and veratridine. Known inhibitors of C1- transport will be added to the incubations to see which type of carrier system is activated by the treatments. Chick embryonic retina is also exquisitely sensitive to excitotoxicity. Developmental aspects of toxicity will be examined by using retina of ages E6 to E21, which correspond to specific stages of development. Results will be correlated with alterations in AA metabolism, both in terms of dynamic measurements using radioactive precursors, the development of enzymes as measured by direct assay and immunohistochemistry. The various inhibitors of C1- transport used in the tissue slice studies will be studied to see which, if any, protect against neurotoxicity. The C1-/HCO3- system also regulates intracellular pH in some cell types. Intracellular pH will be measured in the retinas following treatment with excitotoxins with a method which utilizes radioactive benzoic acid. Studies will also be done with glial cultures from neonatal rat brain and embryonic chick retina. Direct effects of excitotoxins, in the presence and absence of high levels of K+ will be examined, including alterations in C1- uptake and intracellular pH changes. These studies should give positive or negative answers to hypotheses concerning mechanisms underlying excitotoxic sequelae and the role of glia. More importantly, they may give novel directions to studying the interactions of neurons and glia.