Presence of N-Methylated β-Carbolinium Ions and Potential Neurotoxic Analogs of MPP+ in the Brain and Cerebrospinal Fluid of Parkinsonian and Non-Parkinsonian Patients

  • Kazuo Matsubara
  • Michael A. Collins
  • Shotai Kobayashi
  • Atsushi Akane
  • Jun Ikebuchi
  • Setsunori Takahashi
  • Edward J. Neafsey
  • Kojiro Kimura
Part of the Advances in Behavioral Biology book series (ABBI, volume 44)


The etiology of Parkinson’s disease is unknown. N-Methyl-4-phenyl-tetrahydropyridine (MPTP), a contaminant originally found in synthetic “street heroin”, induces Parkinsonian like symptoms which arise from destruction of nigrostriatal neurons.1 After crossing the blood-brain-barrier, MPTP is oxidized intracerebrally in glia or non-dopaminergic neurons by monoamineoxidase B to an intermediate, N-methyl-4-phenyl-dihydropyridium ion, which disproportionates or is spontaneously oxidized to N-methyl-4-phenyl-tetrahydropyridinium ion (MPP+).2–4 The “MPTP story” led to considerations that environmental and/or endogenously generated substances with similar structures to MPTP may undergo brain bioactivation to mitochondrial toxicants. Recent studies have concentrated on iso-quinolines5–9 and β-carbolines (BCs).


Substantia Nigra Parkinsonian Patient Methylation Activity Dopamine Uptake Nigrostriatal Neuron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    J.W. Langston, P. Ballard, J.W. Tetrud, and I. Irwin, Chronic parkinsonism in humans due to a product of meperidine-analog synthesis, Science 219: 979 (1983).PubMedCrossRefGoogle Scholar
  2. 2.
    K. Chiba, A.J. Trevor and N. Castagnoli jr, Active uptake of MPF, a metabolite of MPTP, by brain synaptosomes, Biochem. Biophys. Res. Commun. 128: 1228 (1985).PubMedCrossRefGoogle Scholar
  3. 3.
    S.P. Markey, J.N. Johannessen, C.C. Chiueh, R.S. Bums, and M.A. Herkenham, Intra-neuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism, Nature 311: 464 (1984).PubMedCrossRefGoogle Scholar
  4. 4.
    T.P. Singer, N. Castagnoli Jr, R. Ramsay, and A.J. Trevor, Biochemical events in the development of Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, J. Neurochem. 49: 1 (1987).PubMedCrossRefGoogle Scholar
  5. 5.
    M. Kohno, S. Ohta, and M. Hirobe, Tetrahydroisoquinoline and 1-methyl-tetra hydroisoquinoline as novel endogenous amines in rat brain, Biochem. Biophys. Res. Commun. 140: 448 (1986).PubMedCrossRefGoogle Scholar
  6. 6.
    M. Naoi, S. Matsuura, T. Takahashi, and T. Nagatsu, A N-methyl-transferase in human brain catalyses N-methylation of 1,2,3,4-tetrahydroisoquinoline, a precursor of a dopaminergic neurotoxin, Nmethylisoquinolinium ion, Biochem. Biophys. Res. Commun. 161: 1213 (1989).PubMedCrossRefGoogle Scholar
  7. 7.
    M. Naoi, S. Matsuura, H. Parvez, T. Takahashi, Y. Hirata, M. Minami, and T. Nagatsu, Oxidation of N-methyl-1,2,3,4-tetrahydroisoquinoline into the N-methylisoquinolinium ion by monoamine oxdase, J. Neurochem. 52: 653 (1989).PubMedCrossRefGoogle Scholar
  8. 8.
    W. Maruyama, D. Nakahara, M. Ota, T. Takahashi, A. Takahashi, T. Nagatsu, and M. Naoi, NMethylation of dopamine-derived 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, (R)-salsoinol, in rat brain: in vivo microdialysis study, J. Neurochem. 59: 395 (1992).PubMedCrossRefGoogle Scholar
  9. 9.
    M. Yoshida, T. Niwa, and T. Nagatsu, Parkinsonism in monkeys produced by chronic administration of an endogenous substance of the brain, tetrahydroisoquinolines: the behavioral and biochemical changes, Neurosci. Leu. 119: 109 (1990).CrossRefGoogle Scholar
  10. 10.
    M.A. Collins, and E.J. Neafsey, Beta-carboline analogs of N-methyl-4-phenyl tetrahydropyridine (MPTP): endogenous factors underlying idiopathic parkinsonism?, Neurosci. Lett. 55: 179 (1985).PubMedCrossRefGoogle Scholar
  11. 11.
    M.A. Collins, E.J. Neafsey, B.Y. Cheng, K. Hurley-Giusk, N.A. Ung-Chhun, D.A. Pronger, M.A. Christensen, and D. Hurley-Gius, Endogenous analogs of N-methyl-4-phenyl-tetrahydropyridine: Indoleamine derived tetrahydro-beta-carboline as potential causative factors in Parkinson’s disease, Adv. Neurol. 45: 179 (1986).Google Scholar
  12. 12.
    M.A. Collins, E.J. Neafsey, K. Matsubara, R.J. Cobuzzi Jr, and H. Rollema, Indole-N-methylated ßcarbolinium ions as potential brain-bioactivated neurotoxins, Brain Res. 570: 154 (1992).PubMedCrossRefGoogle Scholar
  13. 13.
    E.J. Neafsey, G. Drucker, K. Raikoff, and M.A. Collins, Striatal dopaminergic toxicity following intranigral injection in rats of 2-methyl-norharman, a ß-carbolinum analog of N-methyl-4phenylpyridinium ion (MPP+), Neurosci. Lett. 105: 344 (1989).PubMedCrossRefGoogle Scholar
  14. 14.
    S.A. Barker, R.E.W. Harrison, J.A. Monti, G.B. Brown, and S.T. Christian, Identification and quantitation of 1,2,3,4-tetrahydro-beta-carboline, and 6-methoxy-1,2,3,4-tetrahydro-beta-carboline as in vivo constituents of rat brain, Biochem. Pharmacol. 30: 9 (1981).PubMedCrossRefGoogle Scholar
  15. 15.
    T.R. Bosin, S. Borg, and K.F. Faull, Harman in rat brain, lung and human CSF: Effect of alcohol consumption, Alcohol 5: 505 (1989).CrossRefGoogle Scholar
  16. 16.
    S. Fukushima, K. Matsubara, A. Alcane, and H. Shiono, 1-Methyl-tetrahydro-ß-carboline-3-carbolxylic acid is present in the rat brain and is not increased after acute injection with cyanamide treatment, Alcohol 9: 31 (1992).PubMedCrossRefGoogle Scholar
  17. 17.
    C.M. Melchior and M.A. Collins, The routes and significance of endogenous synthesis of alkaloids in animal, CRC Crit. Rev. Toxicol. 10: 313 (1982).CrossRefGoogle Scholar
  18. 18.
    P. Peurs, J.V. Johnson, R.A. Yost, and K.F. Faull, Concentrations of tryptoline and methtryptoline in rat brain, J. Neurochem. 52: 847 (1989).CrossRefGoogle Scholar
  19. 19.
    H. Rommelspacher, H. Damm, S. Strauss, and G. Schmidt, Ethanol induces an increase of harman in the brain and urine of rats, Arch. Pharmacol. 327: 107 (1984).CrossRefGoogle Scholar
  20. 20.
    K. Matsubara, M.A. Collins, and E.J. Neafsey, Mono-N-methylation of 1,2,3,4-tetrahydro-ß-carbolines in brain cytosol: absence of indole methylation, J. Neurochem. 59: 505 (1992).PubMedCrossRefGoogle Scholar
  21. 21.
    K. Matsubara, E.J. Neafsey, and M.A. Collins, Novel S-adenosylmethionine-dependent indole-Nmethylation of ß-carbolines in brain particulate fractions, J. Neurochem. 59: 511 (1992).PubMedCrossRefGoogle Scholar
  22. 22.
    G. Drucker, K. Raikoff, E.J. Neafsey, and M.A. Collins, Dopamine uptake inhibitory capacities of potentially endogenous beta-carbolines that are structually related to oxidation product of N-methyl4-phenyltetrahydropyridine (MPTP), Brain Res. 509: 125 (1990).PubMedCrossRefGoogle Scholar
  23. 23.
    R.R. Albores, M.A. Collins, E.J. Neafsey, G. Drucker, and J.Z. Fields, Mitochondrial respiratory inhibition by N-methylated-beta-carboline derivatives structurally resembling N-methyl-4phenylpyridine (MPP+), Proc. Natl. Acad. Sci. 87: 9368 (1990).PubMedCrossRefGoogle Scholar
  24. 24.
    J.M. Fields, R.R. Albores, E.J. Neafsey, and M.A. Collins, Inhibition of mitochondrial succinate oxidation-similarities and differences between N-methylated ß-carbolines and MPP+, Arch. Biochem. Biophys. 294: 539 (1992).PubMedCrossRefGoogle Scholar
  25. 25.
    K. Matsubara, M.A. Collins, A. Alcane, J. Ikebuchi, E.J. Neafsey, M. Kagawa, and H. Shiono, Potential bioactivated neurotoxicants, N-methyulated ß-carbolinium ions, are present in human brain, Brain Res. 610: 90 (1993).PubMedCrossRefGoogle Scholar
  26. 26.
    J.W. Langston, L.S. Forno, C.S. Rebert, and I. Irwin, Selective nigral toxicity after systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the squirrel monkey., Brain Res. 292: 390 (1984).PubMedCrossRefGoogle Scholar
  27. 27.
    K. Matsubara, S. Fukushima, A. Alcane, K. Hama, and Y. Fukui, Tetrahydro-ß-carboline in human urine and rat brain-no evidence of formation by alcohol drinking, Alcohol Alcohol. 21: 339 (1986).PubMedGoogle Scholar
  28. 28.
    H. Rommelspacher and L. Schmidt, Tetrahydro-isoquinolines and ß-carbolines: putative natural substances in plants and mammals, Prog. Drug Res. 29: 415 (1985).PubMedCrossRefGoogle Scholar
  29. 29.
    H. Rommelspacher, H. Damm, S. Lutter, L.G. Schmidt, M. Otto, N. Sachs-Ericsson, and G. Schmidth, Harman (1-methyl-(3-carboline) in blood plasma and erythrocytes of nonalcoholics following ethanol loading, Alcohol 7: 553 (1990).CrossRefGoogle Scholar
  30. 30.
    H. Rommelspacher, L.G. Schmidt, and M. Torsten, Plasma norharman (ß-carboline) levels elevated in chronic alcoholics, Alcohol. Clin. Exp. Res. 15: 553 (1991).PubMedCrossRefGoogle Scholar
  31. 31.
    M. Schouten and J. Bruinvels, Endogenously formed norharman in platelet rich plasma obtained from porphyric rats, Pharmacol. Biochem. Behay., 24: 1219 (1986).CrossRefGoogle Scholar
  32. 32.
    T.R. Bosin, K.F. Fall, and J.D. Barchas. Harman in alcoholic beverages: pharmcological and toxicological implication, Alcohol. Clin. Exp. Res. 12: 679 (1988).PubMedCrossRefGoogle Scholar
  33. 33.
    R. Susilo, H. Damm, H. Rommelspacher, and G. Hófle, Biotransformation of 1-methyl-1,2,3,4tetrahydro-1I-carboline-l-carboxylic acid to harmalan, tetrahydroharman and harman in rats, Neurosci. Lett. 81: 325 (1987).PubMedCrossRefGoogle Scholar
  34. 34.
    J.A. Javitch, R.J. D’Amato, S.M. Strittmatter, and S.H. Snyder, Parkinsonism-inducing neurotoxin, Nmethyl-4-phenyl-1,2,3,6-tetrahydropyridine: uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurones explains selective toxicity, Proc. Natl. Acad. Sci. USA 82: 2173 (1985).PubMedCrossRefGoogle Scholar
  35. 35.
    S.H. Snyder and R.J. D’Amato, MPTP: A Neurotoxin relevant to the pathophysiology of Parkinson’s disease, Neurology 36: 250 (1986).PubMedCrossRefGoogle Scholar
  36. 36.
    C.A.D. Smith, A.C. Gough, P.N. Leigh, E.A. Summers, A.E. Harding, D.M. Maranganore, S. Sturman, A.H.V. Schapira, A. Williams, N.K. Spurr, and C.R. Wolf, Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson’s disease, Lancet 339: 1375 (1992).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Kazuo Matsubara
    • 1
  • Michael A. Collins
    • 2
  • Shotai Kobayashi
    • 3
  • Atsushi Akane
    • 4
  • Jun Ikebuchi
    • 5
  • Setsunori Takahashi
    • 1
  • Edward J. Neafsey
    • 6
  • Kojiro Kimura
    • 1
  1. 1.Legal MedicineShimane Medical UniversityIzumo 693Japan
  2. 2.BiochemistryLoyola University ChicagoMaywoodUSA
  3. 3.Internal Medicine III DepartmentsShimane Medical UniversityIzumo 693Japan
  4. 4.Legal Medicine DepartmentKansai Medical UniversityOsaka 570Japan
  5. 5.Legal Medicine DepartmentTottori UniversityYonago 683Japan
  6. 6.Anatomy DepartmentsLoyola University ChicagoMaywoodUSA

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