Neurotoxins and Monoamine Oxidase B Inhibitors: Possible Mechanisms for the Neuroprotective Effect of (—)-Deprenyl

  • V. Glover
  • M. Sandler
Part of the Milestones in Drug Therapy book series (MDT)


The 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) [1–3] model of Parkinson’s disease, which came to light by the accidental self-administration of this protoxin by a group of American drug addicts, has stimulated an enormous amount of research and speculation into the cause of this disorder and the possible role of endo- or exotoxins in its pathogenesis. The fact that (—)-deprenyl (selegiline), the selective monoamine oxidase (MAO) B inhibitor, both prevents the development of MPTP toxicity [4, 5] and appears to slow degeneration of the nigrostri-atal tract in human idiopathic paralysis agitans has lent support to the idea that analogous toxins may be responsible for Parkinson’s disease (PD). They may well be, although there is no convincing evidence for this conclusion at the present time. However, other explanations for the putative neuroprotective effects of (—)-deprenyl are also possible and will be discussed in this chapter.


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  1. [1]
    Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert C, Kopin IJ. Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1979; 1: 249–254.CrossRefGoogle Scholar
  2. [2]
    Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983; 219: 979–980.CrossRefGoogle Scholar
  3. [3]
    Langston JW, Langston EB, Irwin I. MPTP-induced parkinsonism in human and non-human primates — clinical and experimental aspects. Acta Neurol Scand 1984; 100 (Suppl.): 49–54.Google Scholar
  4. [4]
    Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC. Protection against the dopaminergic neurotoxicity of l-methyl-4-phenyl-l,2,5,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature 1984; 311: 467–469.CrossRefGoogle Scholar
  5. [5]
    Cohen G, Pasik P, Cohen B, Leist A, Mytilineou C, Yahr MD. Pargyline and deprenyl prevent the neurotoxicity of l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys. Europ J Pharmacol 1984; 106: 209–210.CrossRefGoogle Scholar
  6. [6]
    Birkmayer W, Knoll J, Riederer P, Youdim MBH, Hars V, Marton J. Increased life expectancy resulting from addition of l-deprenyl to Madopar treatment in Parkinson’s disease: a long term study. J Neural Transm 1985; 64: 113–127.CrossRefGoogle Scholar
  7. [7]
    Tetrud JW, Langston JW. The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. Science 1989; 245: 519–522.CrossRefGoogle Scholar
  8. [8]
    Parkinson Study Group. Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1989; 321: 1364–1371.CrossRefGoogle Scholar
  9. [9]
    Landau WM. Clinical neuromythology IX. Pyramid sale in the bucket shop: DATATOP bottoms out. Neurology 1990; 40: 1337–1339.CrossRefGoogle Scholar
  10. [10]
    Elsworth JD, Glover V, Reynolds GP, Sandler M, Lees AJ, Phuapradit P, Shaw KM, Stern GM, Kumar P. Deprenyl administration in man; a selective monoamine oxidase B inhibitor without the “cheese effect”. Psychopharmacology 1978; 57: 33–38.CrossRefGoogle Scholar
  11. [11]
    Riggs JE. Parkinson’s disease: an epidemiologic method for distinguishing between symptomatic and neuroprotective treatments. Clin Pharmacol 1991; 14: 489–497.Google Scholar
  12. [12]
    Rinne JO, Röyttä M, Paljärvi L, Rummukainen J, Rinne UK. Selegiline (deprenyl) treatment and death of nigral neurons in Parkinson’s disease. Neurology 1991; 41: 859–861.CrossRefGoogle Scholar
  13. [13]
    Knoll J, Dallo J, Yen TT. Striatal dopamine, sexual activity and lifespan. Longevity of rats treated with (-)deprenyl. Life Sci 1989; 45: 525–531.CrossRefGoogle Scholar
  14. [14]
    Milgram NW, Racine RJ, Nellis P, Mendonca A, Ivy GO. Maintenance on l-deprenyl prolongs life in aged male rats. Life Sci 1990; 47: 415–420.CrossRefGoogle Scholar
  15. [15]
    Knoll J. Striatal dopamine, ageing and (—)deprenyl. Jugoslav Physiol Pharmacol Acta 1986; 22: 261–273.Google Scholar
  16. [16]
    Finnegan KT, Skratt JJ, Irwin I, DeLanney LE, Langston JW. Protection against DSP-4-induced neurotoxicity by deprenyl is not related to its inhibition of MAO B. Europ J Pharmacol 1990; 184: 119–126.CrossRefGoogle Scholar
  17. [17]
    Tatton WG, Greenwood CE. Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism. J Neurosci Res 1991; 30: 666–672.CrossRefGoogle Scholar
  18. [18]
    Salo PT, Tatton WG. Deprenyl reduces the death of motoneurons caused by axotomy. J Neurosci Res 1992; 31: 394–400.CrossRefGoogle Scholar
  19. [19]
    Snyder SH. Parkinson’s disease. Fresh facts to consider. Nature 1991; 350: 195–196.CrossRefGoogle Scholar
  20. [20]
    Hyman C, Hofer M, Barde Y-A, Juhasz M, Yancopoulos GD, Squinto SP, Lindsay RM. BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 1991; 350: 230–232.CrossRefGoogle Scholar
  21. [21]
    Pezzoli G, Zecchinelli A, Ricciardi S, Burke RE, Fahn S, Scarlato G, Carenzi A. Intraventricular infusion of epidermal growth factor restores dopaminergic pathway in hemiparkinsonian rats. Movement Disorders 1991; 6: 281–287.CrossRefGoogle Scholar
  22. [22]
    Knoll J. The pharmacological basis of the beneficial effects of (—)deprenyl (selegiline) in Parkinson’s and Alzheimer’s diseases. J Neural Transm 1992. In press.Google Scholar
  23. [23]
    Feiten DL, Feiten SY, Fuller RW, Romano TD, Smalstig EB, Wong DT, Clemens JA. Chronic dietary pergolide preserved nigrostriatal neuronal integrity in aged Fischer 344 rats. Neurology of Ageing 1992; 13: 339–351.CrossRefGoogle Scholar
  24. [24]
    Lichter P, Kurlan R, Miller C, Shoulson I. Does pergolide slow the progression of Parkinson’s disease? A 7-year follow-up study. Neurology 1988; 38 (Suppl. 1): 122.CrossRefGoogle Scholar
  25. [25]
    Zimmerman T, Sage JI. Long-term pergolide treatment and progression of Parkinson’s disease. Neurology 1989; 39 (Suppl. 1): 200.Google Scholar
  26. [26]
    Glover V, Elsworth JD, Sandler M. Dopamine oxidation and its inhibition by (—)-deprenyl in man. J Neural Transm 1980; 16 (Suppl): 163–172.Google Scholar
  27. [27]
    Glover V, Sandler M, Owen F, Riley GJ. Dopamine is a monoamine oxidase B substrate in man. Nature 1977; 265: 80–81.CrossRefGoogle Scholar
  28. [28]
    Waldmeier PC, Delini-Stula A, Maitre L. Preferential deamination of dopamine by an A type monoamine oxidase in rat brain. Naunyn-Schmiedeberg’s Arch Pharmacol 1976; 292: 9–14.CrossRefGoogle Scholar
  29. [29]
    Neff NH, Garrison CK, Fuentes J. Trace amines and the monoamine oxidases. In: Usdin E, Sandler M, editors. Trace Amines and the Brain. New York: Marcel Dekker 1976; 41–57.Google Scholar
  30. [30]
    Irwin I. The neurotoxin l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP): a key to Parkinson’s disease? Pharm Res 1986; 3: 7–11.CrossRefGoogle Scholar
  31. [31]
    Langston JW. MPTP and Parkinson’s disease. Trends Neurosci 1985; 80: 79–83.CrossRefGoogle Scholar
  32. [32]
    Langston JW, Irwin I. Pyridine toxins. In: Calne DB, editor. Drugs for the Treatment of Parkinson’s Disease. New York: Springer 1989: 205–226.CrossRefGoogle Scholar
  33. [33]
    Gibb C, Willoughby J, Glover V, Sandler M, Testa B, Jenner P, Marsden CD. Analogues of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine as monoamine oxidase substrates: a second ring is not necessary. Neurosci Letters 1987; 76: 316–322.CrossRefGoogle Scholar
  34. [34]
    Basma AN, Heikkila E, Nicklas WJ, Giovanni A, Geller HM. l-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine- and 1 methyl-4-(2,-ethylphenyl) 1,2,3,6-tetrahydropyridine-induced toxicity in PC12 cells: role of monoamine oxidase A. J Neurochem 1990; 55: 870–877.CrossRefGoogle Scholar
  35. [35]
    Nagatsu T, Hirata Y. Inhibition of the tyrosine hydroxylase system by MPTP, 1-methyl-4-phenylpyridinium ion (MPP+) and the structurally related compounds in vitro and in vivo. Europ Neurol 1987; 26 (Suppl. 1): 11.CrossRefGoogle Scholar
  36. [36]
    Yoshida M, Niwa T, Nagatsu T. Parkinsonism in monkeys produced by chronic administration of an endogeneous substance of the brain, tetrahydroisoquinoline: the behavioral and biochemical changes. Neurosci Lett 1990; 119: 109–113.CrossRefGoogle Scholar
  37. [37]
    Niwa T, Takeda N, Sasaoka T, Kaneda N, Hashizume Y, Yoshizumi H, Tatematsu A, Nagatsu T. Detection of tetrahydroisoquinoline in parkinsonian brain as an endogenous amine by use of gas chromatography-mass spectrometry. J Chromatogr 1989; 491: 397–403.CrossRefGoogle Scholar
  38. [38]
    Naoi M, Matsuura S, Takahashi T, Nagatsu T. An N-methyltransferase in human brain catalyses N-methylation of 1,2,3,4-tetrahydroisoquinoline into N-methyl-l,2,3,4-tetra-hydroisoquinoline, a precursor of a dopaminergic neurotoxin, N-methylisoquinolinium ion. Biochem Biophys Res Commun 1989; 161: 1213–1219.CrossRefGoogle Scholar
  39. [39]
    Makino Y, Tasaki Y, Ohta S, Hirobe M. Confirmation of the enantiomers of 1-methyl-1,2,3,4-tetrahydroisoquinoline in the mouse brain and foods applying gas chro-matograph/mass spectrometry with negative ion chemical ionization. Biomed Environ Mass Spectrometry 1990; 19: 415–419.CrossRefGoogle Scholar
  40. [40]
    Makino Y, Tasaki Y, Kashiwasake M, Tachikawa O, Ohta S, Hirobe M. Formation of a novel and neurotoxic tetrahydroisoquinoline derivative, 1,3-dimethyltetrahydroiso-quinoline (l,3DiMeTIQ), a condensation product of amphetamines and acetaldehyde in vivo. In: Nagatsu T, Fisher A, Yoshida M, editors. Basic, Clinical, and Therapeutic Aspects of Alzheimer’s and Parkinson’s Disease. New York: Plenum Press, 1990: 325–328.CrossRefGoogle Scholar
  41. [41]
    Takahashi T, Naoi M, Ichinose H, Kojima T, Nagatsu T. Food-derived heterocyclic amines as potent inhibitors of catecholamine metabolism. In: Nagatsu T, Fisher A, Yoshida M, editors. Basic, Clinical, and Therapeutic Aspects of Alzheimer’s and Parkinson’s Disease. New York: Plenum Press, 1990: 345–348.CrossRefGoogle Scholar
  42. [42]
    Cohen G, Spina MB. Deprenyl suppresses the oxidant stress associated with increased dopamine turnover. Ann Neurol 1989; 26: 689–690.CrossRefGoogle Scholar
  43. [43]
    Knoll J. The striatal dopamine dependency of life span in male rats. Longevity study with (—)deprenyl. Mech Ageing Devel 1988; 46: 237–262.CrossRefGoogle Scholar
  44. [44]
    Carillo M-C, Kanai S, Nokubu M, Kitani K. (—)Deprenyl induces activities of both superoxide dismutase and catalase but not of glutathione peroxidase in the striatum of young male rats. Life Sci 1991; 48: 517–521.CrossRefGoogle Scholar
  45. [45]
    Clow A, Hussain T, Glover V, Sandler M, Dexter DT, Walker M. (—)-Deprenyl can induce soluble superoxide dismutase in rat striata. J Neural Transm 1991; 86: 77–80.CrossRefGoogle Scholar
  46. [46]
    Glover V, Halket JM, Watkins PJ, Clow A, Goodwin BL, Sandler M. Isatin: identity with the purified endogeneous monoamine oxidase inhibitor tribulin. J Neurochem 1988; 51: 656–659.CrossRefGoogle Scholar
  47. [47]
    Watkins P, Clow A, Glover V, Halket J, Przyborowska A, Sandler M. Isatin, regional distribution in rat brain and tissues. Neurochem Int 1990; 17: 321–323.CrossRefGoogle Scholar
  48. [48]
    Tolmasoff JM, Ono T, Cutler RG. Superoxide dismutase: correlation with life-span and specific metabolic rate in primate species. Proc Nat Acad Sci USA 1980; 77: 2777–2781.CrossRefGoogle Scholar
  49. [49]
    Sohal RS, Farmer KJ, Allen RG. Correlates of longevity in two strains of the housefly, Musca domestica. Mech Ageing Devel 1987; 40: 171–179.CrossRefGoogle Scholar
  50. [50]
    Kellog EW, Fridovich I. Superoxide dismutase in the rat and mouse as a function of age and longevity. J Gerontol 1976; 4: 405–408.CrossRefGoogle Scholar
  51. [51]
    Przedborski S, Kostic V, Jackson-Lewis V, Carlson E, Epstein CJ, Cadet JL. Transgenic mice expressing the human SOD gene are resistant to MPTP-induced toxicity. Soc Neurosci Abstr 1990; 16: 1260.Google Scholar
  52. [52]
    Albino-Teixeira A, Azevedo I, Martel F, Osswald W. Superoxide dismutase partially prevents sympathetic denervation by 6-hydroxydopamine. Arch Pharmacol 1991; 344: 36–40.Google Scholar
  53. [53]
    Ceballos I, Lafon M, Javoy Agid F, Hirsch E, Nicole A, Simet P, Agid Y. Superoxide dismutase and Parkinson’s disease. Lancet 1990; i: 1035–1036.CrossRefGoogle Scholar

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© Springer Basel AG 1993

Authors and Affiliations

  • V. Glover
  • M. Sandler

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