GLUTAMATE, EXCITOTOXINS AND NEURONAL-GLIAL INTERACTIONS

推测氨基酸(AA)的功能或代谢异常 谷氨酸(GLU)和GABA的神经递质参与了 几种神经系统疾病的病因或后遗症，例如亨廷顿氏症 舞蹈症、帕金森氏病、癫痫和某些形式的 橄榄桥小脑萎缩。此外，GLU类似物，例如 兴奋毒素海人酸(KA)，当直接注射到大鼠脑区时， 导致神经元死亡，增加了内源性的有趣的可能性 兴奋性毒性活动可能与这种紊乱有关。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起作用。两种可能 KA毒性的拮抗剂，乙酰唑胺(AZ)，(一种碳酸酐酶 抑制剂)和谷氨酸类似物α-氨基甲酸酯(AP)将被 对它们衰减的确切机制进行了深入的研究 体外兴奋毒性作用(如受体拮抗剂、代谢 相互作用)以及它们是否与其他去偏振剂相互作用 如藜芦碱或K+。谷氨酸、天冬氨酸、谷氨酰胺和GABA的代谢 将在体内不同脑区进行研究，并在体外进行小脑研究 以及用这些药物治疗后的海马片。数据将是 根据神经元和胶质细胞对新陈代谢的贡献进行评估 并仔细研究他们如何行动的线索。碳酸酐酶可能是 与神经胶质细胞中的二氧化碳固定有关。因此，14C-小苏打 在AZ存在的情况下代谢成氨基酸也会 调查过了。AZ特别有趣，因为它是一种临床上的 有效的抗惊厥剂，其作用方式尚不清楚。在……里面 此外，AZ和AP将在体内应用于大鼠，看看它们是否 抑制或减弱KA及相关化合物的兴奋毒性作用 直接注射到大脑的各个区域。研究工作亦会继续进行。 中枢神经系统谷氨酸代谢关键酶的研究。使用抑制剂、药物和 各种组织制剂，谷氨酸脱氢酶(GDH)将被研究 是否与神经递质AA池有关。此外, 反应方向(即谷氨酸氧化脱氨或 2-羟基戊二酸的还原胺化反应)及其原位反应速率 已经确定了。希望这项提案中描述的实验 将导致研究中枢神经系统正常和疾病状态的新方法。

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.