Summary
N-Methyl(R)salsolinol, an endogenous neurotoxin, has been proposed to be closely involved in the pathogenesis of Parkinson's disease. The selective toxicity to dopaminergic neurons was strictly limited for (R)-enantiomer of N-methylsalsolinol. Its precursor, (R)salsolinol was enzymatically synthesized from dopamine and acetaldehyde in human. However, it has never been examined whether a non-enzymatic reaction produces racemic salsolinol derivatives from dopamine especially in patients under L-DOPA therapy. To clarify the point, their contents were examined in intraventricular fluid from parkinsonian patients administrated with L-DOPA. Only (R)-enantiomer of N-methylsalsolinol and very low concentration of salsolinol could be detected. The results suggest that N-methyl(R)salsolinol synthesis may not depend on dopamine level, but on the activity of enzymes related to its synthesis and/or catabolism. The results are discussed in relation to pathogenesis Parkinson's disease.
Similar content being viewed by others
References
Bembenek ME, Abell CW, Chrisey LA, Rozwadoeska MD, Gesner W, Brossi A (1990) Inhibition of monoamine oxidase A and B by simple isoquinoline alkaloids; racemic and optically active 1,2,3,4-tetrahydro-3,4-dihydro, and fully aromatic isoquinolines. J Med Chem 33: 147–152
Blennow K, Wallin A, Gottfries CG, Mansson JE, Svennerholm L (1993) Concentration gradients for monoamine metabolites in lumbar cerebrospinal fluid. J Neural Transm [P-D Sect] 5: 5–15
Dostert P, Strolin Benedetti M, Dedieu M (1987) Ratio of enantiomers of salsolinol in human urine. Pharmacol Toxicol 60 [Suppl] 1: 13
Dostert P, Strolin Benedett M, Dordain G, Vernay D (1989) Enantiomeric composition of urinary salsolinol in Parkinsonian patients after Madopar. J Neural Transm [P-D Sect] 1: 61–74
Maruyama W, Nakahara D, Ota M, Takahashi T, Takahashi A, Nagatsu T, Naoi M (1992) N-Methylation of dopamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, (R)-salsolinol, in rat brains: in vivo microdialysis study. J Neurochem 59: 395–400
Maruyama W, Dostert P, Matsubara K, Naoi M (1995) N-Methyl(R)salsolinol produces hydroxyl radicals: involvement to neurotoxicity. Free Rad Biol Med 19: 67–75
Maruyama W, Abe T, Tohgi H, Dostert P, Naoi M (1996a) A dopaminergic neurotoxin, (R)-N-methylsalsolinol, increases in parkinsonian CSF. Ann Neurol (in press)
Maruyama W, Naoi M, Narabayashi H (1996b) The mechanism of L-DOPA and L-threo-3,4-dihydroxyphenylserine and their effects on monoamines in the human brain: analysis of the intraventricular fluid from parkinsonian patients. J Neurol Sci (in press)
Matsubara K, Kobayashi S, Kobayashi Y, Yamashita K, Koida H, Hatta M, Iwamoto K, Tanaka O, Kimura K (1995) β-Carbolinium cations, endogenous MPP+ analogues, in the lumbar cerebrospinal fluid of patients with Parkinson's disease. Neurology 45: 2240–2245
Moser A, Scholz J, Nobbe F, Vieregge P, Böhme V, Bamberg H (1995) Presence of N-methyl-norsalsolinol in the CSF: correlation with dopamine metabolites of patients with Parkinson's disease. J Neurol Sci 131: 183–189
Naoi M, Maruyama W, Dostert P (1994) Binding of 1,2(N)-dimethyl-6,7-dihydroxyisoquinolinium ion to melanin: effects of ferrous and ferric ion on the binding. Neurosci Lett 171: 9–12
Naoi M, Maruyama W, Dostert P (1995a) Dopamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines; oxidation and neurotoxicity. In: Yu P, Tipton KF, Boulton AA (eds) Progress in brain research, vol 106. Elsevier, Amsterdam, pp 227–239
Naoi M, Maruyama W, Zhang JH, Takahashi T, Deng Y, Dostert P (1995b) Enzymatic oxidation of the dopaminergic neurotoxin, 1(R), 1(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, into 1,2(N)-dimethyl-6,7-dihydroxyisoquinolinium ion. Life Sci 57: 1061–1066
Naoi M, Maruyama W, Dostert P, Hashizume Y, Nakahara D, Takahashi T, Ota M (1996a) Dopamine-derived endogenous 1(R),2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, N-methyl-(R)-salsolinol, induced parkinsonism in rat: biochemical, pathological and behavioral studies. Brain Res 709: 285–295
Naoi M, Maruyama W, Dostert P, Hashizume Y (1996b) Animal model of Parkinson's disease induced by naturally-occurring 1(R), 2(N)-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline. Biogen Amines 12: 135–147
Niwa T, Takeda N, Yoshizumi H, Tatematsu A, Yoshida M, Dostert P, Naoi M, Nagatsu T (1991) Presence of 2-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline and 1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, novel endogenous amines, in parkinsonian and normal brains. Biochem Biophys Res Commun 177: 603–609
Origitano T, Hannigan J, Collins MA (1981) Rat brain salsolinol and blood-brain barrier. Brain Res 224: 446–451
Sällström Baum S, Rommelspacher H (1994) Determination of total dopamine, R- and S- salsolinol in human plasma by cyclodextrin bonded-phase liquid chromatography with electrochemical detection. J Chromatogr B 660: 235–241
Takahashi T, Deng Y, Maruyama W, Dostert P, Kawai M, Naoi M (1994) Uptake of a neurotoxin-candidate, (R)-1,2-dimethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline into human dopaminergic neuroblastoma SH-SY5Y cells by dopamine transport system. J Neural Transm [GenSect] 98: 107–118
Teitel S, O'Brien J, Brossi A (1972) Alkaloids in mammalian tissue II. Synthesis of (+) and (−)substituted-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinolines. J Med Chem 15: 845–846
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Maruyama, W., Narabayashi, H., Dostert, P. et al. Stereospecific occurrence of a parkinsonism-inducing catechol isoquinoline, n-methyl(R)salsolinol, in the human intraventricular fluid. J. Neural Transmission 103, 1069–1076 (1996). https://doi.org/10.1007/BF01291791
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01291791