Formation and Metabolism of Salsolinol Enantiomers

Jackson State University, Jackson MS

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Abstract

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an exogenous (synthetic) neurotoxin inducing[unreadable] Parkinsonism in humans, non-human primates, and rats. Salsolinol (6,7-dihydroxy-1-methyl-1, 2, 3, 4[unreadable] -tetrahydroisoquinoline, Sal) is an MPTP-like neurotoxin. Some of its phase I metabolites, e.g. N-methyl-[unreadable] (R)-Sal, have been shown to target and injure particularly dopaminergic nigrostriatal neurons inducing[unreadable] Parkinsonism. Unfortunately, Sal can be formed in vivo from the condensation of dopamine (a[unreadable] neurotransmitter in the brain) and acetaldehyde (a metabolite of alcohol). Very interestingly, the two[unreadable] enantiomers of N-methyl-Sal exhibit distinct neurotoxicological properties. N-methyl-(R)-Sal induces[unreadable] Parkinsonism in rats, but N-methyl-(S)-Sal does not. However, the stereochemical aspects of in-vivo[unreadable] formation and metabolism of these neurotoxic enantiomers remain largely unknown. For[unreadable] example, literature data on the stereospecific occurrence of Sal in physiological fluids are[unreadable] inconsistent. The goal of this research is to identify the biosynthetic and metabolic pathways of[unreadable] Sal enantiomers. To this end, the development of suitable analytical methodology for[unreadable] simultaneous quantification of the enantiomers of Sal and its phase I metabolites is needed. We[unreadable] are proposing to develop a chiral analytical method based on capillary HPLC /tandem mass[unreadable] spectrometry for this purpose. After the analytical methodology is in place, studies will be carried[unreadable] out: 1) to determine the enantiomeric compositions of endogenous Sal and its metabolites in rat[unreadable] brain and physiological fluids; 2) to investigate in vivo formation of Sal in rat brain using[unreadable] microdialysis after administering 13C labeled acetaldehyde and pyruvic acid to rats; 3) to profile[unreadable] the phase I metabolites of Sal and N-methyl-Sal using 13C labeled Sal or N-methyl-Sal[unreadable] enantiomers (e.g. [1 ,m-13C2]-salsolinol); and 4) to assess the neurotoxicity of enantiomeric Sal[unreadable] and its major phase I metabolites including N-methyl-Sal and N-methyl-4-hydroxyl-Sal in PC-12[unreadable] and SH-SY5Y cells. The hypothesis is that racemization of the more neurotoxic (R)-enantiomers[unreadable] of endogenous Sal and its metabolites is a major pathway leading to detoxification in a healthy[unreadable] nervous system. By using the improved methodology for chiral analysis in combination with in[unreadable] vivo microdialysis and stable isotope labeling techniques, the research will contribute significantly[unreadable] to our knowledge of in vivo formation and metabolism of these neurotoxins involved in the[unreadable] pathogenesis of certain neurodegenerative disorders such as Parkinson's disease. From these[unreadable] studies, significant gains will also be made in understanding the stereochemical aspects of[unreadable] neurotoxicity in general.