N-methyl(R)salsolinol produces hydroxyl radicals: involvement to neurotoxicity

Recently, (R)-1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [N-methyl-(R)salsolinol, NM(R)Sal] and 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion [DiMeDHIQ+] were found to cause a syndrome similar to parkinsonism in rodents. NM(R)Sal is produced in the brain by N-methylation of a naturally occurring catechol isoquinoline, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline [(R)salsolinol, (R)Sal], which is formed from dopamine. The mechanism of NM(R)Sal cytotoxicity to dopamine neurons was examined using in vitro experiments. NM(R)Sal was found to be nonenzymatically oxidized into DiMeDHIQ+, with concomitant formation of hydroxyl radicals. The oxidation and the radical production were completely inhibited by the antioxidants, ascorbic acid and reduced glutathione, and the radical formation was enhanced by Fe(II) and, to a less extent, by Fe(III). The oxidation of NM(R)Sal into DiMeDHIQ+ and the production of hydroxyl radicals may be essential for neurotoxicity to develop in dopamine neurons. The possible involvement of this catechol isoquinoline in the pathogenesis of Parkinson's disease is discussed.