Cerebrospinal fluid 3,4-dihydroxyphenylacetic acid level after tolcapone administration as an indicator of nigrostriatal degeneration.
Cerebrospinal fluid 3,4-dihydroxyphenylacetic acid level after tolcapone administration as an indicator of nigrostriatal degeneration.
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托卡朋给药后脑脊液 3,4-二羟基苯乙酸水平作为黑质纹状体变性的指标。
DOI：
10.1016/s0014-4886(03)00140-7
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发表时间：
2003
影响因子：
5.3
通讯作者：
DiMonte,DonatoA
中科院分区：
文献类型：
--
作者：
Thiffault,Christine;Langston,JWilliam;DiMonte,DonatoA
从实验和临床角度来看，黑质纹状体变性的可靠生物标记物的开发具有重要意义，因为此类生物标记物可用于帕金森病模型以及帕金森病患者的诊断和监测目的。在这项研究中，测量了正常松鼠猴和帕金森松鼠猴的脑脊液（CSF）中多巴胺代谢物3,4-二羟基苯乙酸（DOPAC）的水平，以评估其作为黑质纹状体损伤指标的可靠性。特别是，我们测试了这样的假设：通过抑制儿茶酚胺-O-甲基转移酶 (COMT) 活性，从而阻止 DOPAC 转化为高香草酸，这些测量可能会变得更加准确。口服 COMT 抑制剂托卡朋（2 剂，每次 15 mg/kg，间隔 4 小时）显着降低猴脑中的酶活性。托卡朋治疗可提高未损伤动物以及由 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 引起的严重黑质纹状体多巴胺能损伤后出现帕金森病的猴子的 CSF DOPAC 浓度（约四倍）。然而，重要的是，COMT 抑制极大地放大了对照猴和帕金森猴之间 CSF DOPAC 水平的差异，因为 MPTP 诱导的 DOPAC 消耗在不存在托卡朋的情况下为 35%，而在存在托卡朋的情况下为 >60%。因此，托卡朋给药增强了 CSF 中 DOPAC 的检测，并由此提高了 CSF DOPAC 作为黑质纹状体变性标志物的可靠性。
The development of reliable biological markers of nigrostriatal degeneration has important implications from both experimental and clinical viewpoints, since such biomarkers could be used for diagnostic and monitoring purposes in models of parkinsonism as well as in Parkinson’s disease patients. In this study, levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) were measured in the cerebrospinal fluid (CSF) of normal and parkinsonian squirrel monkeys in order to assess their reliability as indicators of nigrostriatal injury. In particular, we tested the hypothesis that these measurements may become more accurate by inhibiting catecholamine-O-methyltransferase (COMT) activity and therefore blocking the conversion of DOPAC to homovanillic acid. Oral administration of the COMT inhibitor tolcapone (2 doses of 15 mg/kg each with a 4-h interval) significantly reduced enzyme activity in the monkey brain. Tolcapone treatment enhanced CSF DOPAC concentrations in unlesioned animals (by approximately four times) as well as monkeys rendered parkinsonian after severe nigrostriatal dopaminergic injury caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Importantly, however, COMT inhibition greatly magnified the differences in CSF DOPAC levels between control and parkinsonian monkeys, since MPTP-induced DOPAC depletion was 35% in the absence vs >60% in the presence of tolcapone. Thus, tolcapone administration enhances the detection of DOPAC in the CSF and, by doing so, improves the reliability of CSF DOPAC as a marker of nigrostriatal degeneration.