NEUROTOXIC PROPERTIES OF A SEROTONIN OXIDATION PRODUCT: POSSIBLE ROLE IN ALZHEIMER'S DISEASE
NEUROTOXIC PROPERTIES OF A SEROTONIN OXIDATION PRODUCT: POSSIBLE ROLE IN ALZHEIMER'S DISEASE
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DOI：
10.1097/00002093-198802030-00090
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发表时间：
1989
影响因子：
2.1
通讯作者：
Ladislav Volicer;Jin-Chung Chen;P. B. Crino;Vogt Ba;J. Fishman;J. Rubins;Schenepper Pw;N. Wolfe
中科院分区：
文献类型：
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作者：
Ladislav Volicer;Jin-Chung Chen;P. B. Crino;Vogt Ba;J. Fishman;J. Rubins;Schenepper Pw;N. Wolfe
研究了5-羟色胺（5-HT）的部分氧化形式4，5-二酮色胺（4，5-DKT）的性质。将4，5-DKT施用到侧脑室（i. c. v.）结果表明，大鼠海马CA 1、CA 3和齿状回区的内嗅、岛叶和后扣带皮层细胞死亡，终末变性。此外，静脉注射4，5-DKT导致前额叶皮层、纹状体和海马中5-HT和5-羟基吲哚乙酸（5-HIAA）水平显著降低。将4，5-DKT注射到扣带回和海马皮质中导致这些结构中的细胞死亡和终末变性。在脑碎片灌流和孵育实验中，4，5-DKT剂量依赖性地增加大鼠海马和纹状体5-HT的流出。多巴胺及其代谢产物3，4-二羟基苯乙酸从纹状体的流出不受影响。在海马制备物中，氟西汀使4，5-DKT刺激的5-HT外排减少24%，帕吉林对其无影响。4，5-DKT选择性结合纯化的鸟嘌呤核苷酸结合蛋白，并抑制百日咳毒素催化的核糖基化在1 nM-1 μ M浓度。通过16通道高压液相色谱法结合库仑检测分析脑脊液（CSF），未证实Alzheimer CSF中存在4，5-DKT，但检测到几个峰，在对照组和Alzheimer CSF中显著不同，这是由未知化合物引起的。
Properties of a partially oxidized form of serotonin (5-HT), 4,5-diketotryptamine (4,5-DKT), synthesized by electrochemical oxidation of 5-HT, were investigated. Administration of 4,5-DKT into the lateral ventricles (i.c.v.) of rats resulted in cell death and terminal degeneration in entorhinal, insular, and posterior cingulate cortices, and in the CA1, CA3 and dentate gyrus sectors of hippocampus. Furthermore, i.c.v. administration of 4,5-DKT resulted in a significant depletion of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels in prefrontal cortex, striatum and hippocampus. 4,5-DKT injection into cingulate and hippocampal cortices resulted in cell death and terminal degeneration in these structures. In brain fragment perfusion and incubation experiments, 4,5-DKT increased dose dependently 5-HT efflux from rat hippocampus and striatum. The efflux of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid from striatum was unaffected. In hippocampal preparations, fluoxetine decreased 4,5-DKT-stimulated efflux of 5-HT by 24%, and pargyline did not affect it. In vitro, 4,5-DKT bound covalently to nucleophilic -SH groups in glutathione and mercaptoethanol and the binding was blocked by N-ethyl-maleimide. 4,5-DKT bound selectively to purified guanine nucleotide binding proteins, and inhibited pertussis toxin-catalyzed ribosylation at 1nM-1 microM concentrations. Analysis of cerebrospinal fluid (CSF) by a 16-channel high pressure liquid chromatography with coulometric detection did not confirm presence of 4,5-DKT in Alzheimer CSF, but detected several peaks, significantly different in control and Alzheimer CSF, which were caused by unknown compounds.