Occurrence and Neurotoxicity of Tetrahydroisoquinolines

描述(由申请人提供)：四氢异喹啉的存在和神经毒性本研究的目标是鉴定和定量大鼠脑中的某些MPTP样四氢异喹啉(TIQ)对映体。此外，还将评估这些TIQ对映体和主要代谢物的神经毒性。已观察到TIQ神经毒性的手性。例如，6，7-二羟基-1，2-二甲基-1，2，3，4-四氢异喹啉(N-甲基沙龙醇)的两个对映体表现出不同的神经毒理学特性：(R)-对映体诱导大鼠帕金森氏症，而(S)-对映体不诱导。然而，这些对映体神经毒素的体内形成和代谢在很大程度上仍不清楚。为了进行这些研究，需要在痕量水平上同时量化立体异构体。然而，缺乏合适的分析方法。为了获得分析能力，我们计划改进我们开发的用于测定丹参素对映体的手性GC-MS方法，并建立基于毛细管电色谱质谱(CEC-MS)的手性方法。实验将包括：a)。同时测定大鼠脑组织中多巴胺和TIQ对映体，包括(R)-/(S)-沙龙醇和N-甲基-(R)-/(S)-沙龙醇；用~(13)C标记的丹参素对映体(即[1，m-13C2]-丹参素)定量研究丹参素的代谢；c)研究化学刺激对生物合成和代谢的影响；以及d)评估某些TIQ的单个对映体及其代谢物对大鼠的神经毒性。我们的假设是，内源性沙龙醇和N-甲基沙龙醇的神经毒性(R)对映体的外消旋是导致健康神经系统解毒的主要途径，一些化学物质如酒精可以阻止外消旋。通过对MPTP样TIQ神经毒素的体内对映体生物合成、代谢和神经毒性的研究，有助于我们了解TIQ神经毒性的手性和帕金森病的发病机制。

DESCRIPTION (provided by applicant): Occurrence and Neurotoxicity of Tetrahydroisoquinolines The goal of this research is to identify and quantify certain MPTP-like tetrahydroisoquinoline(TIQ) enantiomers in rat brain. Further, the neurotoxicity of these TIQ enantiomers and the major metabolites will be assessed. The chirality of TIQ's neurotoxicity has been observed. For example, the two enantiomers of 6,7-dihydroxy-1, 2-dimethyl-1,2, 3, 4 -tetrahydroisoquinoline (N-methyl-salsolinol) exhibit different neurotoxicological properties: the (R)-enantiomer induces Parkinsonism in rats, but the (S)-enantiomer does not. However, the in-vivo formation and metabolism of these enantiomeric neurotoxins remain largely unknown. To carry out these studies, simultaneous quantifications of the stereoisomers at trace levels are needed. However, suitable analytical methodology is lacking. To obtain the analytical capability, we plan to modify the chiral GC-MS method that we have developed for the determination of salsolinol enantiomers, and also to develop a chiral method based on capillary electrochromatography -mass spectroscopy (CEC-MS). Experiments will include: a). simultaneous determination of dopamine and TIQ enantiomers including (R)-/(S)-salsolinol and N-methyl-(R)-/(S)-salsolinol in rat brain; b). quantitative studies of salsolinol metabolism using 13C labeled salsolinol enantiomers (i.e. [1,m-13C2]-salsolinol); c) studies of the effects of chemical stimuli on the biosynthesis and metabolism; and d) assessment of the neurotoxicity of individual enantiomers of certain TIQs and their metabolites to rats. Our hypothesis is that racemization of the neurotoxic (R)-enantiomers of endogenous salsolinol and N-methylsalsolinol is a major pathway leading to detoxification in a healthy nervous system, and the racemization can be hindered by some chemical species such as alcohol. By studying the in-vivo enantiomeric biosynthesis, metabolism, and the neurotoxicity of MPTP-like TIQ neurotoxins, this research will contribute to our understanding of the chirality of TIQ neurotoxicity and the pathogenesis of Parkinson's disease.