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.

R15NS044177

2003-02-01

2008-01-31