GLUTAMATE, EXCITOTOXINS AND NEURONAL-GLIAL INTERACTIONS

假定氨基酸（AA）的功能或代谢异常 谷氨酸（GLU）和GABA的神经递质，已被牵连在 几种神经系统疾病的病因或后遗症，例如，亨廷顿氏病 舞蹈病、帕金森病、癫痫和某些形式的 橄榄体脑桥小脑萎缩 此外，Glu类似物，例如，的 兴奋毒素红藻氨酸（KA），当直接注射到大鼠脑区时， 引起神经元死亡，这就提出了一种有趣的可能性， 兴奋性毒性活性可能与这些疾病有关。 研究表明 能量代谢的改变和正常的神经胶质细胞 GLU的代谢可能在这种神经毒性中发挥作用。 两个可能 KA毒性拮抗剂乙酰唑胺（AZ）（一种碳酸酐酶 抑制剂）和α-氨基庚二酸盐（AP），谷氨酸类似物，将被 深入研究了它们衰减的确切机制 体外兴奋性毒性作用（例如，受体拮抗剂，代谢的 相互作用）以及它们是否与其他去极化剂相互作用， 如藜芦碱或K+。 GLU、天冬氨酸、谷氨酰胺和GABA的代谢 将在体内不同脑区和体外小脑中进行研究 和海马脑片的变化。 数据将 根据神经元和神经胶质对该代谢的贡献进行评价 仔细观察它们的行为 碳酸酐酶可以是 与神经胶质细胞中的CO2固定有关。 因此，14 C-碳酸氢盐 在AZ的存在下，代谢成氨基酸也将是可能的。 研究了 AZ特别有趣，因为它是一种临床上 有用的抗惊厥药，其作用方式尚不清楚。 在 此外，AZ和AP将在体内给予大鼠，以观察它们是否 抑制或减弱KA和相关化合物的兴奋毒性作用 直接注射到大脑的各个区域 研究还将继续进行。 对中枢葡萄糖代谢关键酶的影响。 使用抑制剂，药物和 将研究各种组织制剂，谷氨酸脱氢酶（GDH） 是否与神经递质AA库有关。 此外，本发明还提供了一种方法， 反应的方向（即，谷氨酸的氧化脱氨基作用，或 2-酮戊二酸酯的还原胺化），其原位速率将为 确定。 希望本提案中描述的实验 将为研究中枢神经系统的正常和疾病状态提供新的方法。

Aberrations of function or metabolism of the putative amino acid (AA) neurotransmitters of glutamate (GLU) and GABA, have been implicated in the etiology or sequelae of several neurological disorders, e.g., Huntington's chorea, Parkinson's disease, epilepsy and certain forms of olivopontocerebellar atrophy. In addition, GLU-analogs, e.g., the excitotoxin kainic acid (KA), when injected directly into rat brain areas, cause neuronal death, raising the intriguing possibility that endogenous excitotoxic activity may be involved in such disorders. Studies have shown that an alteration in energy metabolism and the normal neuronal-glial metabolism of GLU may play a role in this neurotoxicity. Two possible antagonists of KA toxicity, acetazolamide (AZ), (a carbonic anhydrase inhibitor) and Alpha-aminopimelate (AP), a glutamate analogue, will be intensively studied as to the exact mechanism by which they attenuate excitotoxic effects in vitro (e.g., receptor antagonists, metabolic interactions) and whether they interact with other depolarizing agents such as veratridine or K+. Metabolism of GLU, aspartate, glutamine and GABA will be studied in vivo in various brain areas and in vitro in cerebellar and hippocampal slices after treatment with these drugs. Data will be evaluated in terms of neuronal and glial contributions to that metabolism and scrutinized for clues as to how they act. Carbonic anhydrase may be associated with CO2 fixation in glial cells. Therefore, 14C-bicarbonate metabolism into amino acids in the presence of AZ will also be investigated. AZ is especially interesting in that it is a clinically useful anticonvulsant whose mode of action is not well understood. In addition, AZ and AP will be administered to rats in vivo to see if they inhibit or attenuate the excitotoxic action of KA and related compounds injected directly into various brain areas. Studies will also be continued on key enzymes of GLU metabolism in CNS. Using inhibitors, drugs and various tissue preparations, glutamate dehydrogenase (GDH), will be studied as to whether it is involved with neurotransmitter AA pools. In addition, the direction of reaction (i.e., oxidative deamination of glutamate or reductive amination of 2-oxoglutarate) and its rate in situ will be ascertained. It is hoped that the experiments described in this proposal will lead to novel ways of studying normal and diseased states in the CNS.