Different action on dopamine catabolic pathways of two endogenous 1,2,3,4-tetrahydroisoquinolines with similar antidopaminergic properties
Different action on dopamine catabolic pathways of two endogenous 1,2,3,4-tetrahydroisoquinolines with similar antidopaminergic properties
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DOI：
10.1046/j.1471-4159.2001.00391.x
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发表时间：
2001-07-01
影响因子：
4.7
通讯作者：
Vetulani, J
中科院分区：
文献类型：
--
作者：
Antkiewicz-Michaluk, L;Michaluk, J;Vetulani, J
采用高效液相色谱法和电化学检测法，研究了1-甲基-1，2，3，4-四氢异喹啉(1MeTIQ)和1-苄基-1，2，3，4-四氢异喹啉(1BnTIQ)对大鼠三个脑区多巴胺及其代谢物高香草酸(HVA)、3，4-二羟基苯乙酸(DOPAC)和3-甲氧基酪胺(3MT)浓度的影响。通过计算适当代谢物与多巴胺浓度的比率，评估纹状体中沿着N-氧化和O-甲基化途径的多巴胺分解代谢率。此外，还观察了急性给药1MeTIQ和1BnTIQ后小鼠的自发活动、阿朴吗啡刺激的运动活动和肌肉僵直程度。我们发现1MeTIQ在单次和长期给药后并没有改变所有被研究结构中的多巴胺和HVA的水平。然而，多巴胺中间代谢物DOPAC和3MT的水平受到明显影响。DOPAC水平显著降低(60-70%)，而神经元外代谢产物3MT水平显著升高(170-200%)。与1MeTIQ相比，1BnTIQ可降低多巴胺水平(约60%)，增加总代谢物HVA水平。(40%)，尤其是在纹状体，但DOPAC和3MT水平没有变化。结果表明，1MeTIQ和1BnTIQ对多巴胺分解代谢有不同的影响。潜在的神经保护化合物1MeTIQ不改变总的多巴胺分解代谢速率，它强烈地抑制依赖单胺氧化酶(MAO)的分解代谢途径，显著激活依赖于儿茶酚-O-甲基转移酶(COMT)的O甲基化。相反，具有潜在神经毒性活性的化合物1BnTIQ可显著增加多巴胺的代谢率，并强烈激活氧化MAO依赖的分解代谢途径。有趣的是，这两个化合物产生了相似的抗多巴胺能功能作用：拮抗阿朴吗啡过度活动和诱导肌肉僵直。这一结果可能解释了内源性脑四氢异喹啉衍生物神经保护和神经毒性的生化基础。
The effect of single and multiple 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) administration on concentrations of dopamine and its metabolites: homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxytyramine (3MT) in three brain areas was studied HPLC with electrochemical detection in Wistar rats. The rate of dopamine catabolism in the striatum along the N-oxidative and O-methylation pathways was assessed by calculation of the ratio of appropriate metabolites to dopamine concentration. In addition, the spontaneous and apomorphine-stimulated locomotor activity, and muscle rigidity was studied after acute administration of 1MeTIQ and 1BnTIQ. We have found that 1MeTIQ did not change the level of dopamine and HVA in all investigated structures both after a single and chronic administration. However, the levels of intermediary dopamine metabolites, DOPAC and 3MT, were distinctly affected. The level of DOPAC was strongly depressed (by 60-70%) while the level of extraneuronal matabolite 3MT was significantly elevated (by 170-200%). In contrast to 1MeTIQ, 1BnTIQ depressed the level of dopamine (by approximately 60%) and increased the level of total metabolite, HVA. (by 40%) especially in the striatum, but the levels of DOPAC and 3MT remained unchanged. The paper has shown that 1MeTIQ and 1BnTIQ produced different effects on dopamine catabolism. Potential neuroprotective compound 1MeTIQ did not change the rate of total dopamine catabolism, it strongly inhibited the monoamine oxidase (MAO)-dependent catabolic pathway and significantly activated the catechol-O-methyltransferase (COMT)-dependent O methylation. In contrast 1BnTIQ, a compound with potential neurotoxic activity, produced the significant increase of the rate of dopamine metabolism with strong activation of the oxidative MAO-dependent catabolic pathway. Interestingly, both compounds produced similar antidopaminergic functional effects: antagonism of apomorphine hyperactivity and induction of muscle rigidity. The results may explain the biochemical basis of the neuroprotective and of the neurotoxic properties endogenous brain tetrahydroisoquinoline derivatives.