The Therapeutic Place and Value of Present and Future MAO-B Inhibitors — l-Deprenyl as the Gold Standard

  • P. Riederer
  • M. B. H. Youdim
Part of the Milestones in Drug Therapy book series (MDT)


The establishment of MAO inhibitors in the early 1960s failed, not because of the lack of intended efficacy but because of accompanying side-effects, e.g., hypotension and hypertension, psychic alteration, and hepatotoxicity. With Johnston’s discovery in 1968 of the multiple forms (MAO-A, MAO-B), selective MAO inhibitors could be developed for the first time that considered substrate specificity. Thus, there was hope to reduce the initially observed side-effects. l-Deprenyl (selegiline), synthesized by Ecsery and developed as an antidepressant drug by Knoll, was such a substance. As an antidepressant l-deprenyl did not succeed, but as an anti-Parkinson drug it did [1]. Meanwhile, l-deprenyl has become the “gold standard” of MAO inhibitors. The clinical and theoretical innovations of the last decade have been decisively marked by l-deprenyl since it unites many synergistic biochemical and pharmacological properties. Any new MAO-B inhibitor must have comparable properties since they determine the therapeutic value. Some of these new inhibitors will be reviewed here in comparison to l-deprenyl.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    Birkmayer W, Riederer P, Youdim MBH, Linauer W. The potentiation of the anti-akinetic effect after L-dopa treatment by an inhibitor of MAO-B, Deprenyl. J Neural Transm, 1975; 36: 303–326.CrossRefGoogle Scholar
  2. [2]
    Riederer P, Jellinger K, Seemann D. Monoamine oxidase and parkinsonism. In: Tipton KF, Dostert P, Strolin-Benedetti M, editors. Monoamine Oxidase and Disease. London: Academic Press, 1984: 403–415.Google Scholar
  3. [3]
    Birkmayer W, Riederer P, Ambrozi L, Youdim MBH. Implications of combined treatment with “Madopar” and l-deprenyl in Parkinson’s disease — A long-term study. Lancet, 1977; i: 439–443.CrossRefGoogle Scholar
  4. [4]
    Paterson IA, Juorio AV, Boulton AA. Possible mechanism of action of deprenyl in parkinsonism. Lancet, 1992; i: 183.Google Scholar
  5. [5]
    Paterson I A, Berry MD, Juorio AV. (—) Deprenyl and dopamine transmission: electrophysiological recordings in the rat caudate nucleus. Soc Neurosci Abstr. In press.Google Scholar
  6. [6]
    Levitt P, Pintar JE, Breakfield XO. Immunocytochemical demonstration of monoamine oxidase B in brain astrocytes and serotoninergic neurons. Proc Natl Acad Sci USA, 1982; 79: 6385–6389.CrossRefGoogle Scholar
  7. [7]
    Konradi C, Kornhuber J, Frölich L, Fritze J, Heinsen H, Beckmann H, Schulz E, Riederer P. Demonstration of monoamine oxidase-A and B in the human brainstem by a histochemical technique. Neurosci, 1989; 33: 383–400.CrossRefGoogle Scholar
  8. [8]
    Konradi C, Riederer P, Heinsen H. Histochemistry of MAO subtypes in the brainstem of humans: a relation to the radical hypothesis of Parkinson’s disease? In: Przuntek H, Riederer P, editors. Early Diagnosis and Preventive Therapy in Parkinson’s Disease. Key Topics in Brain Research. New York, Vienna: Springer-Verlag, 1989: 243–248.CrossRefGoogle Scholar
  9. [9]
    Melamed E. Chronic levodopa suppresses its own utilization in striatum. In: Rinne UK, Nagatsu T, Horowski R, editors. How to Proceed Today in Treatment. Proceedings International Workshop Berlin Parkinson’s Disease. Medicom Europe, 1991: 206–215.Google Scholar
  10. [10]
    Rinne UK. Early use of dopamine agonist in the treatment of Parkinson’s disease. In: Rinne UK, Nagatsu T, Horowski R, editors. How to Proceed Today in Treatment. Proceedings International Workshop Berlin Parkinson’s Disease. Medicom Europe, 1991: 326–336.Google Scholar
  11. [11]
    Cohen G. Monoamine oxidase, hydrogen peroxide, and Parkinson’s disease. In: Yahr MD, Bergmann KJ, editors. Advances in Neurology. New York: Raven Press, 1986: 119–125.Google Scholar
  12. [12]
    Cohen G, Spina MB. Deprenyl suppresses the oxidant stress associated with increased dopamine turnover. Ann Neurol, 1989; 26: 689–690.CrossRefGoogle Scholar
  13. [13]
    Fornstedt B, Brun A, Rosengren E, Carlsson A. The apparent autoxidation rate of catechols in dopamine-rich regions of human brains increases with the degree of depigmentation of substantia nigra. J Neural Transm [PD Sect], 1989; 1: 279–295.CrossRefGoogle Scholar
  14. [14]
    Gerlach M, Riederer P, Youdim MBH. The molecular pharmacology of l-deprenyl. Europ J Pharmacol — Mol Pharmacol Sect, 1992; 226: 97–108.CrossRefGoogle Scholar
  15. [15]
    Jarman J, Glover V, Sandler M, Turjanski N, Stern G. Platelet monoamine oxidase B activity in Parkinson’s disease: A re-evaluation. J Neural Transm [PDSect]. In press.Google Scholar
  16. [16]
    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
  17. [17]
    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
  18. [18]
    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
  19. [19]
    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
  20. [20]
    Milgrana 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
  21. [21]
    Aquilonius SM, Jossan SS, Ekblom JG, Askmark H, Gillberg PG. Increased binding of l-deprenyl in spinal cords from patients with amyotrophic lateral sclerosis as demonstrated by autoradiography. J Neural Transm [Gen Sect]. 1992; 89: 111–122.CrossRefGoogle Scholar
  22. [22]
    Paterson IA, Juorio AV, Boulton AA. 2-Phenylethylamine: a modulator of catecholamine transmission in the mammalian central nervous system? J Neurochem, 1990; 55: 1827.CrossRefGoogle Scholar
  23. [23]
    Reynolds GP, Riederer P, Sandler M, Jellinger K, Seemann D. Amphetamine and 2-phenylethylamine in post-mortem parkinsonian brain after (—)deprenyl administration. J Neural Transm, 1978; 43: 271–277.CrossRefGoogle Scholar
  24. [24]
    Elsworth JD, Sandler M, Lees AJ, Ward C, Stern GM. The contribution of amphetamine metabolites of (—)-deprenyl to its antiparkinsonian properties. J Neural Transm, 1982; 54: 105–110.CrossRefGoogle Scholar
  25. [25]
    Birkmayer W, Riederer P. Die Parkinson-Krankheit. Biochemie, Klinik, Therapie, 2nd ed. Vienna, New York: Springer Verlag, 1985.CrossRefGoogle Scholar
  26. [26]
    Rinne JO, Röyttä M, Paljärvi L, Rummukainen J, Rinne UK. Selegiline (deprenyl) treatment and death of nigral neurons in Parkinson’s disease. Neurol, 1991; 41: 859–861.CrossRefGoogle Scholar
  27. [27]
    Davis GC, Williams AC, Markey SP, Ebert MH, Calne ED, Reichert C, Kopin IJ. Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiat Res, 1979; 1: 249–254.CrossRefGoogle Scholar
  28. [28]
    Burns RS, Chiuen CC, Markey SP, Ebert MH, Jacobowitz D, Kopin I. A primate model of Parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine. Proc Natl Acad Sci USA, 1983; 80: 4544–4551.Google Scholar
  29. [29]
    Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC. Protection against the dopaminergic neurotoxicity of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine by monoamine oxidase inhibitors. Nature, 1984; 311: 467–469.CrossRefGoogle Scholar
  30. [30]
    Riederer P, Youdim MBH. Monoamine oxidase activity and monoamine metabolism in brains of parkinsonian patients treated with l-deprenyl. J Neurochem, 1986; 46: 1359–1365.CrossRefGoogle Scholar
  31. [31]
    Gerlach M, Riederer P, Przuntek H, Youdim MBH. MPTP mechanisms of neurotoxicity and their implications for Parkinson’s disease. Europ J Pharmacol — Mol Pharmacol Sect, 1991; 208: 273–286.CrossRefGoogle Scholar
  32. [32]
    Barbeau A, Roy M, Cloutier T, Plasse L, Paris S. Environmental and genetic factors in the etiology of Parkinson’s disease. In: Yahr MD, Bergmann KJ, editors. Advances in Neurology. New York: Raven Press, 1986: 299–306.Google Scholar
  33. [33]
    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
  34. [34]
    Heikkila RE, Cohen G. Further studies on generation of hydrogen peroxide by 6-hy-droxydopamine: potentiation by ascorbic acid. Mol Pharmacol, 1972; 8: 241.Google Scholar
  35. [35]
    Sachs CH, Jonsson G. Mechanism of action of 6-hydroxydopamine. Pharmacol 1975; 24: 1.Google Scholar
  36. [36]
    Graham DG. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quiñones. Mol Pharmacol, 1978; 14: 333–343.Google Scholar
  37. [37]
    Ben-Shachar D, Eshel G, Finberg JPM, Youdim MBH. The iron chelator desferoxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J Neurochem, 1991; 56: 1441–1447.CrossRefGoogle Scholar
  38. [38]
    Knoll J. The possible mechanism of action of (-)deprenyl in Parkinson’s disease. J Neural Transm, 1978; 43: 177–198.CrossRefGoogle Scholar
  39. [39]
    Knoll J. Striatal dopamine, ageing and (-)deprenyl. Jugoslav Physiol Pharmacol Acta, 1986; 22: 261–273.Google Scholar
  40. [40]
    Knoll J. R-(-)-deprenyl (selegiline, Movergan®) facilitates the activity of the nigrostriatal dopaminergic neuron. J Neural Transm [Suppl], 1987; 25: 45–66.Google Scholar
  41. [41]
    Carillo MC, 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 Sc, 1991; 48: 517–521.CrossRefGoogle Scholar
  42. [42]
    Clow A, Hussain T, Glover V, Sandler M, Walker M, Dexter D. Pergolide can induce soluble superoxide dismutase in rat striata. J Neural Transm [Gen Sect]. 1991; 86: 77–80.CrossRefGoogle Scholar
  43. [43]
    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
  44. [44]
    Birkmayer W, Knoll J, Riederer P, Youdim MBH. (—)Deprenyl leads to prolongation of L-dopa efficacy in Parkinson’s disease. Modern Problems of Pharmacopsychiatry, Vol 19. Basel: Karger, 1983: 170–176.Google Scholar
  45. [45]
    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: 113–117.CrossRefGoogle Scholar
  46. [46]
    Tetrud JW, Langston JW. The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. Science, 1989; 245: 519–522.CrossRefGoogle Scholar
  47. [47]
    DATATOP (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
  48. [48]
    Landau WM. Clinical neuromythology IX. Pyramid scale in the bucket shop: DATATOP bottoms out. Neurol, 1990; 40: 1337–1339.Google Scholar
  49. [49]
    Green R, Youdim MBH. Use of a behavioral model to study the action of monoamine oxidase inhibition in vivo. In: Monoamine Oxidase and Its Inhibition (Ciba Foundation Symposium 39). Amsterdam: Elsevier, 1976: 231–246.Google Scholar
  50. [50]
    Elsworth JD, Glover V, Reynolds GP, Sandler M, Lees AJ, Phuapradit P, et al. Deprenyl administration in man; a selective monoamine oxidase B inhibitor without the “cheese effect”. Psychopharmacol, 1978; 57: 33–38.CrossRefGoogle Scholar
  51. [51]
    Sofic E, Lange KW, Jellinger K, Riederer P. Reduced and oxidized glutathione in the substantia nigra in Parkinson’s disease. Neurosci Lett. 1992; 142: 128–130.CrossRefGoogle Scholar
  52. [52]
    Olney JW, Price MT, Labruyere J, Salles KS, Friedrich G, Mueller M, et al. Anti-parkin- sonian agents are pheneyelidine agonists and N-methyl-aspartate antagonists. Europ J Pharmacol, 1987; 142: 319–325.CrossRefGoogle Scholar
  53. [53]
    Kornhuber J, Bormann J, Retz W, Hübers M, Riederer P. Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex. Europ J Pharmacol, 1989; 166: 589–590.CrossRefGoogle Scholar
  54. [54]
    Kornhuber J, Bormann J, Hübers M, Rusche K, Riederer P. Effects of the 1-amino- adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study. Europ J Pharmacol — Mol Pharmacol Sect, 1991; 206: 297–300.CrossRefGoogle Scholar
  55. [55]
    Youdim MBH, Ben-Shachar D, Riederer P. The role of monoamine oxidase, iron-melanin interaction and intracellular calcium in Parkinson’s disease. J Neural Transm [Suppl], 1990; 32: 239.Google Scholar
  56. [56]
    Furukawa S, Shinoda I, Furukawa Y. Regulatory mechanisms of nerve growth factor synthesis in vitro. Human Cell, 1989; 6 (2): 137–142.Google Scholar
  57. [57]
    Finberg JPM, Sabbagh A, Youdim MBH. Pharmacology of selective propargyl “suicide” inhibitors of monoamine oxidase. In: Usdin E, Sourkes TL, Youdim MBH, editors. Enzymes and Neurotransmitters in Mental Disease. Chichester: Wiley, 1980: 205.Google Scholar
  58. [58]
    Kalir A, Sabbagh A, Youdim MBH. Selective acetylenic “suicide” and reversible inhibitors of monoamine oxidase types A and B. Br J Pharmacol, 1981; 73: 55–62.CrossRefGoogle Scholar
  59. [59]
    Da Prada M, Kettler R, Keller HH, Cesura Am, Richard JG, Marti JS et al. From moclobemide to Ro 19–6327 and Ro 41–1049: the development of a new class of reversible, selective MAO-A and MAO-B inhibitors. J Neural Transm [Suppl], 1990; 29: 279–292.Google Scholar
  60. [60]
    Zerika M, Fozard JR, Dudley MW, Bey P, McDonald IA, Palfreyman MG. MDL 72974: a potent and selective enzyme-activated irreversible inhibitor of monoamine oxidase type B with potential for use in Parkinson’s disease. J Neural Transm (PD Sect.), 1989; 1: 243–254.CrossRefGoogle Scholar
  61. [61]
    Tariot PN, Cohen RM, Sunderland T, Newhouse PA, Yount D, Mellow AM et al. l-(-)Deprenyl in Alzheimer’s disease. Arch Gen Psychiat, 1987a; 44: 427–433.CrossRefGoogle Scholar
  62. [62]
    Tariot PN, Sunderland T, Weingartner H, Murphy DL, Welkowitz JA, Thompson K et al. Cognitive effect of l-deprenyl in Alzheimer disease. Psychopharmacol, 1987b; 91: 489–495.CrossRefGoogle Scholar
  63. [63]
    Tariot PN, Sunderland T, Cohen RM, Newhouse PA, Mueller EA, Murphy DL. Tranylcypromine compared with l-deprenyl in Alzheimer disease. J Clin Psychopharma- col, 1988; 8: 23–27.Google Scholar
  64. [64]
    Martini E, Pataky J, Szilagyi K, Venter V. Brief information on an early phase-II study with (-)deprenyl in demented patients. Pharmacopsychiat, 1987; 20: 256–257.CrossRefGoogle Scholar
  65. [65]
    Piccinin GL, Finali GC, Piccirilli M. Neuropsychological effects of l-deprenyl in Alzheimer’s type dementia. Clin Neuropharmacol, 1990; 13: 147–163.CrossRefGoogle Scholar
  66. [66]
    Mangoni A, Grassi MP, Frattoli L, Piolti R, Bassi S, Motta A et al. Effects of a MAO-B inhibitor in the treatment of Alzheimer disease. Eur Neurol, 1991; 31: 100–107.CrossRefGoogle Scholar
  67. [67]
    Goad DL, Davis CM, Leim P, Fuselier CC, McCormack JR, Olsen KM. The use of selegiline in Alzheimer’s patients with behavior problems. J Clin Psychiat, 1991; 52: 342–345.Google Scholar

Copyright information

© Springer Basel AG 1993

Authors and Affiliations

  • P. Riederer
  • M. B. H. Youdim

There are no affiliations available

Personalised recommendations