COMPARATIVE SEROTONIN NEUROTOXICITY OF THE STEREOISOMERS OF FENFLURAMINE AND NORFENFLURAMINE
COMPARATIVE SEROTONIN NEUROTOXICITY OF THE STEREOISOMERS OF FENFLURAMINE AND NORFENFLURAMINE
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DOI：
10.1016/0091-3057(90)90133-3
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发表时间：
1990-05-01
影响因子：
3.6
通讯作者：
NICHOLS, DE
中科院分区：
文献类型：
--
作者：
JOHNSON, MP;NICHOLS, DE
将芬氟拉明和去甲芬氟拉明的光学异构体给予大鼠，以检查它们破坏5-羟色胺神经元的相对效力。在单次10 mg/kg SC注射四种化合物之一后一周处死大鼠，并通过HPLC-EC技术检查额叶皮质和海马脑区中的单胺和代谢物水平。此外，测定了[3 H]-帕罗西汀与这些脑区匀浆的结合。随着d-芬氟拉明治疗后海马5-HT水平的排泄，在用芬氟拉明和norfenfluramine的d-对映体治疗后，测定的所有多巴胺能标记物均减少。在用芬氟拉明或去甲芬氟拉明的l-对映体治疗后，在该剂量下未观察到任何肾上腺素能标记物的减少。此外，没有一种药物治疗导致儿茶酚胺或其代谢产物显著减少。在检查了所有血清素标记物后，发现d-去甲芬氟拉明比d-芬氟拉明引起的下降幅度显着更大。这些结果的意义进行了讨论的假设，观察到与d-芬氟拉明的长期cardionergic赤字可能会导致其代谢产物，d-norfenfluramine。
The optical isomers of fenfluramine and norfenfluramine were administered to rats to examine their relative potency for destruction of serotonin neurons. Rats were sacrificed one week following a single 10 mg/kg SC injection of one of the four compounds and monoamine and metabolite levels in the frontal cortex and hippocampus brain regions were examined by HPLC-EC techniques. In addition, [3H]-paroxetine binding to homogenates of these brain regions was determined. With the excretion of hippocampal 5-HT levels following d-fenfluramine treatment, there was a decrease in all the serotonergic markers assayed, following treatment with the d-enantiomers of fenfluramine and norfenfluramine. No decrease in any serotonergic marker was seen at this dose following treatment with the l-enantiomers of fenfluramine or norfenfluramine. Also, none of the drug treatments resulted in a significant decrease in catecholamines or their metabolites. With all the serotonergic markers examined, d-norfenfluramine was found to cause a significantly greater decrease than d-fenfluramine. The significance of these results is discussed in terms of the hypothesis that the long-term serotonergic deficits observed with d-fenfluramine may result from its metabolite, d-norfenfluramine.