Occurrence and Neurotoxicity of Tetrahydroisoquinolines

描述（由申请人提供）：四氢异喹啉的发生和神经毒性本研究的目的是鉴定和定量大鼠脑中某些MPTP样四氢异喹啉（TIQ）对映体。此外，将评估这些TIQ对映异构体和主要代谢产物的神经毒性。TIQ的神经毒性具有手性。例如，6，7-二羟基-1，2-二甲基-1，2，3，4 -四氢异喹啉（N-甲基-猪毛菜醇）的两种对映异构体表现出不同的神经毒理学性质：（R）-对映异构体诱导大鼠帕金森病，但（S）-对映异构体不会。然而，这些对映体神经毒素的体内形成和代谢仍然是未知的。为了进行这些研究，需要同时定量痕量水平的立体异构体。然而，缺乏适当的分析方法。为了获得分析能力，我们计划修改手性GC-MS方法，我们已经开发了用于测定猪毛菜醇对映体，并开发了基于毛细管电色谱-质谱（CEC-MS）的手性方法。实验将包括：a）。同时测定大鼠脑中多巴胺和TIQ对映体，包括（R）-/（S）-猪毛菜醇和N-甲基-（R）-/（S）-猪毛菜醇; B）.使用13 C标记的猪毛菜醇对映体（即[1，m-13 C2]-猪毛菜醇）进行猪毛菜醇代谢的定量研究; c）化学刺激对生物合成和代谢的影响的研究;和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，内源性猪毛菜醇和N-甲基猪毛菜醇的神经毒性（R）-对映体的外消旋化是导致健康神经系统中解毒的主要途径，并且外消旋化可以被一些化学物质如酒精阻碍。通过研究MPTP样TIQ神经毒素的体内对映体生物合成、代谢和神经毒性，本研究将有助于我们理解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.