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Neurobiochemie und Wirkmechanismus von Selegilin

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Neuro-Psychopharmaka Ein Therapie-Handbuch
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Zusammenfassung

Da Selegilin bisher der einzige für die Parkinson-Therapie zugelassene MAO-B-Hemmstoff ist, wird im folgenden Absatz vorwiegend nur auf die Mechanismen eingegangen, die dessen klinischen Effekt erklären können. Dieser Wirkstoff wurde ursprünglich nur deshalb für eine Erprobung in der Parkinson-Therapie ausgewählt, weil er in verschiedenen experimentellen pharmakologischen Versuchsmodellen nur eine geringe Verstärkung der sympathikomimetischen Wirkung von Tyramin zeigte (zur übersicht: Finberg und Tenne 1982) und deshalb eine geringe Wahrscheinlichkeit für das Auftreten des „Cheese Effektes“ zu erwarten war. Später wurde erkannt, daß die regionale und zelluläre Verteilung der MAO im Gehirn, das Verhältnis beider Isoformen im Gehirn, die Substrat-Spezifität und die Hemmstoff-Sensitivität unterschiedlich sind zwischen der Ratte (dem Tier, mit dem fast alle präklinischen Untersuchungen durchgeführt wurden) und dem Menschen (Squires 1972, Youdim et al.

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Literatur

  • Alston TA (1981) Suicide substrates for mitochondrial enzymes. Pharmacol Ther 12: 1–41

    Article  PubMed  CAS  Google Scholar 

  • Bach AWJ, Lan NC, Johnson DL, Abell CW, Bem-Benek ME, Kwan SW, Seeburg PH, Shih JC (1988) cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties. Proc Natl Acad Sci USA 85: 4934–4938

    Article  PubMed  CAS  Google Scholar 

  • Benakis A (1985) Pharmacokinetic and metabolic data of Jumex® in human volunteers. In: Mar-Ton J, Zak F, Szebeni R (eds) Proceedings of the International Symposium on (-)-Deprenyl, Jumex®. Chinoin Pharmaceutical and Chemical Works, Budapest, pp 33–37

    Google Scholar 

  • Bench CJ, Price GW, Lammertsma AA (1991) Measurement of human cerebral monoamine oxidase type B (MAO-B) activity with positron emission tomography (PET): a dose ranging study with the reversible inhibitor Ro 19-6327. Eur J Pharmacol 40: 169–173

    Article  CAS  Google Scholar 

  • Bentué-Ferrer D, Menard G, Allain H (1996) Monoamine oxidase B inhibitors. Current status and future potential. CNS Drugs 6: 217–236

    Article  Google Scholar 

  • Biagini G, Zoll M, Fuxe K, Agnati LF (1993) L-deprenyl increases GFAB immunoreactivity selectively in activated astrocytes in rat brain. NeuroReport 5: 955–958

    Article  Google Scholar 

  • Biagini G, Frasoldati A, Fuxe K, Agnati LF (1994) The concept of astrocyte-kinetic drug in the treatment of neurodegenerative diseases: evidence for L-deprenyl-induced activation of reactive astrocytes. Neurochem Int 25: 17–22

    Article  PubMed  CAS  Google Scholar 

  • Bieck PR (1989) Hypertensive Krisen unter reversiblen Hemmstoffen der Monoaminoxidase? Ergebnisse von Tyramin-Interaktionsstudien. Psychiatr Prax 16 [Sonderheft]: 25–31

    PubMed  Google Scholar 

  • Birkmayer W, Riederer P, Youdim MBH, Linauer W (1975) The potentiation of the antiakinetic effect after L-dopa treatment by an inhibitor of MAO-B, deprenyl. J Neural Transm 36: 303–326

    Article  PubMed  CAS  Google Scholar 

  • Blackwell B, Marley E, Price J, Taylor D (1967) Hypertensive interactions between monoamine inhibitors and foodstuffs. Br J Psychiatry 113: 349–365

    Article  PubMed  CAS  Google Scholar 

  • Clow A, Freestone C, Lewis E, Dexter S, Sandler M, Glover V (1993) The effect of pergolide and MDL 72974 on rat brain CuZn superoxide dismutase. Neurosci Lett 164: 41–43

    Article  PubMed  CAS  Google Scholar 

  • Chrisp P, Mammen GJ, Sorkin EM (1991) Selegiline: a review of its pharmacology, symptomatic benefits and protective potential in Parkinson’s disease. Drugs Aging 1: 228–248

    Article  PubMed  CAS  Google Scholar 

  • Denney RM, Patel NT, Fritz RR, Abell CW (1982) A monoclonal antibody elicited to human platelet monoamine oxidase. Isolation and specificity for human monoamine oxidase B but not A. Mol Pharmacol 22: 500–508

    PubMed  CAS  Google Scholar 

  • Dulery BD, Schoun J, Zreika M, Dow J, Hueber N, Hinze C, Haegele KD (1993) Pharmacokinetics of and monoamine oxidase B inhibition by (E)-4-fluoro-ß-fluoromethylene benzene bu-taneamine in man. Arzneimittelforschung 43: 297–302

    PubMed  CAS  Google Scholar 

  • Elsworth JD, Glover V, Reynolds GP, Sandler M, Lees AJ, Phuapradit P, Shaw KM, Stern GM, Kumar P (1978) Deprenyl administration in man; a selective MAO-B inhibitor without the „cheese“ effect. Psychopharmacology 57: 33–38

    Article  PubMed  CAS  Google Scholar 

  • Elsworth JD, Sandler M, Lees AJ, Ward C, Stern GM (1982) The contribution of amphetamine metabolites of (-)-deprenyl to its antiparkinsonian properties. J Neural Transm 54: 105–110

    Article  PubMed  CAS  Google Scholar 

  • Finberg JPM, Tenne M (1982) Relationship between tyramine potentiation and selective inhibition of monoamine oxidase type A and B in the rat vas deferens. Br J Pharmacol 77: 13–21

    Article  PubMed  CAS  Google Scholar 

  • Finberg JPM, Tenne M, Youdim MBH (1981) Tyramine antagonistic properties of AGN 1135, an irreversible inhibitor of monoamine oxidase type B. Br J Pharmacol 73: 65–74

    Article  PubMed  CAS  Google Scholar 

  • Finnegan KT, Skratt JJ, Irwin I, Delanney LE, Langston JW (1990) Protection against DSP-induced neurotoxicity by deprenyl is not related to its inhibition of MAO B. Eur J Pharmacol 184: 119–126

    Article  PubMed  CAS  Google Scholar 

  • Fowler JS, Macgregor RR, Wolf AP, Arnett CD, Dewey SL, Schlyer D, Christman D, Logan J, Smith M, Sachs H, Aquilonius SM, Bjurling P, Halldin C, Hartwig P, Leenders KL, Lundquist H, Oreland L, Stalnacke C-G, Langstrom B (1987) Mapping human brain monoamine oxidase A and B with 11C-labeled suicide in-activators and positron emission tomography. Science 235: 481–485

    Article  PubMed  CAS  Google Scholar 

  • Fowler JS, Volkow ND, Logan J, Schlyer DJ, Macgregor RR, Wang G-J, Wolf AP, Pappas N, Alexoff D, Shea C, Dorflinger E, Yoo K, Morawsky L, Fazzini E (1993) Monoamine oxidase B (MAOB) inhibitor therapy in Parkinson’s disease: the degree and reversibility of human brain MAO-B inhibition by Ro 196327. Neurology 43: 1984–1992

    Article  PubMed  CAS  Google Scholar 

  • Fowler JS, Volkow ND, Logan J, Wang GJ, Macgregor RR, Schlyer D, Wolf AP, Pappas N, Alexoff D, Shea C, Dorflinger E, Kruchowy L, Yoo K, Fazzini E, Patlak C (1994) Slow recovery of human brain MAO after L-deprenyl (selegiline) withdrawal. Synapse 18: 86–93

    Article  PubMed  CAS  Google Scholar 

  • Gerlach M, Riederer P (1993a) Human brain MAO. In: Yasuhara H, Parvez SH, Oguchi K, Sandler M, Nagatsu T (eds) Monoamine oxidase: basic and clinical aspects. VSP, Utrecht, pp 147–158

    Google Scholar 

  • Gerlach M, Riederer P (1993b) Gibt es biochemische Marker der Parkinson-Krankheit? In: Fischer PA (Hrsg) Parkinson-Krankheit. Verlaufsbezogene Diagnostik und Therapie. Editiones Roche, Basel Grenzach-Wyhlen, S 3–17

    Google Scholar 

  • Gerlach M, Riederer P (1996) Animal models of Parkinson’s disease: an empirical comparison with the phenomenology of the disease in man. J Neural Transm 103: 987–1041

    Article  PubMed  CAS  Google Scholar 

  • Gerlach M, Riederer P, Przuntek H, Youdim MBH (1991) MPTP mechanisms of neurotoxicity and their implications for Parkinson’s disease. Eur J Pharmacol [Mol Pharmacol Sect] 208: 273–286

    Article  PubMed  CAS  Google Scholar 

  • Gerlach M, Riederer P, Youdim MBH (1992) The molecular pharmacology of L-deprenyl. Eur J Pharmacol [Mol Pharmacol Sect] 226: 97–108

    Article  PubMed  CAS  Google Scholar 

  • Gerlach M, Riederer P, Youdim MBH (1996a) Molecular mechanisms for neurodegenera-tion: synergism between reactive oxygen species, calcium and excitotoxic amino acids. In: Battistin L, Scarlato G, Caraceni T, Ruggieri S (eds) Parkinson’s disease. Lippincott-Raven, Philadelphia New York, pp 177–194 (Adv Neurol 69)

    Google Scholar 

  • Gerlach M, Youdim MBH, Riederer P (1996b) Pharmacology of selegiline. Neurology 47[Suppl 3]: S137–S145

    Article  PubMed  CAS  Google Scholar 

  • Gibson CJ (1987) Inhibition of MAO B, but not MAO A, blocks DSP-4 toxicity on central NE neurons. Eur J Pharmacol 141: 135–138

    Article  PubMed  CAS  Google Scholar 

  • Giulian D, Vaca K, Corpuz M (1993) Brain glia release factors with opposing actions upon neuronal survival. J Neurosci 13: 29–37

    PubMed  CAS  Google Scholar 

  • Götz ME, Breithaupt W, Sautter J, Kupsch A, Schwarz J, Oertel WH, Youdim MBH, Riederer P, Gerlach M (1998) Chronic TVP-1012 (Ras-agiline) dose-activity response of monoamine oxidases A and B in the brain of the common marmoset. J Neural Transm [Suppl] 52: 271–276

    Article  Google Scholar 

  • Green AR, Mitchell B, Tordorff A, Youdim MBH (1977) Evidence that dopamine deamination by both type A and type B monoamine oxidase in rat brain in vivo and for the degree of enzyme inhibition necessary to increase functional activity of dopamine and 5-hydroxy-tryptamine. Br J Pharmacol 60: 343–349

    Article  PubMed  CAS  Google Scholar 

  • Heinonen EH, Myllylä V, Sotaniemi K, Lamintausta R, Salonen JS, Anttila M, Savijärvi M, Kotila M, Rinne UK (1989) Pharmacokinetics and metabolism of selegiline. Acta Neurol Scand 126: 93–99

    CAS  Google Scholar 

  • Henriot S, Kuhn C, Kettler R, Da Prada M (1994) Lazabemide (Ro 19-6327), a reversible and highly sensitive MAO-B inhibitor: preclinial and clinical findings. J Neural Transm [Suppl] 41: 321–325

    CAS  Google Scholar 

  • Holford NH, Guentert TW, Dingemanse J, Kett-Ler R (1994) Pharmacodynamics of lazabemide, a reversible and selective inhibitor of monoamine oxidase B. Br J Clin Pharmacol 37: 553–557

    Article  PubMed  CAS  Google Scholar 

  • Hou JGG, Lin LFH, Mytilineou C (1996) Glial cell line-derived neurotrophic factor exerts neurotrophic effects on dopaminergic neurons in vitro and promotes their survival and re-growth after damage by 1-methyl-4-phenyl-pyridinium. J Neurochem 66: 74–82

    Article  PubMed  CAS  Google Scholar 

  • Huie RE, Padmaja S (1993) The reaction rate of nitric oxide with superoxide. Free Rad Res Commun 18: 195–199

    Article  CAS  Google Scholar 

  • Johnston JP (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 17: 1285–1297

    Article  PubMed  CAS  Google Scholar 

  • Knoll J (1987) R-(-)-deprenyl (Selegiline, Movergan®) facilitates the activity of the nigrostriatal dopaminergic neuron. J Neural Transm 25 [Suppl]: 45–66

    CAS  Google Scholar 

  • Knoll J (1988) The striatal dopamine dependency of life span in male rats, longevity study with (-)deprenyl. Mech Ageing Dev 46: 237–262

    Article  PubMed  CAS  Google Scholar 

  • Knoll J, Magyar K (1972) Some puzzling effects of monoamine oxidase inhibitors. Adv Biochem Psychopharmacol 5: 393–408

    PubMed  CAS  Google Scholar 

  • Konradi C, Svoma E, Jellinger K, Riederer P, Den-Ney R, Thibault J (1988) Topographic immu-nocytochemical mapping of monoamine oxi-dase-A, monoamine oxidase-B and tyrosine hydroxylase in human post mortem brain stem. Neurosci 26: 791–802

    Article  CAS  Google Scholar 

  • Koutsilieri E, O’callaghan JFX, Chen TS, Riederer P, Rausch W-D (1994) Selegiline enhances survival and neunte outgrowth of MPP+-treat-ed dopaminergic neurons. Eur J Pharmacol [Mol Pharmacol Sect] 269: R3–R4

    Article  PubMed  CAS  Google Scholar 

  • Koutsilieri E, Chen T-S, Rausch W-D, Riederer P (1996) Selegiline is neuroprotective in primary brain cultures treated with 1-methyl-4-phenyl-pyridinium. Eur J Pharmcol [Mol Pharmacol Sect] 306: 181–186

    Article  CAS  Google Scholar 

  • Lindsay RM, Wiegand SJ, Altar CA, Distefano PS (1994) Neurotrophic factors: from molecule to man. Trends Neurol Sci 17: 182–190

    Article  CAS  Google Scholar 

  • Magyar K (1994) Behaviour of (-)-deprenyl and its analogues. J Neural Transm [Suppl] 41:167–175

    CAS  Google Scholar 

  • Magyar K, Tothfalusi L (1984) Pharmacokinetic aspects of deprenyl effects. Pol J Pharmacol Pharm 36: 373–384

    PubMed  CAS  Google Scholar 

  • Mcgeer PL, Mcgeer EG, Suzuki JS (1977) Aging and extrapyramidal function. Arch Neurol 34: 33–35

    Article  PubMed  CAS  Google Scholar 

  • Mcgeer PL, Itagaki S’, Akiyama H, Mcgeer EG (1988) Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol 24: 574–576

    Article  PubMed  CAS  Google Scholar 

  • Mytilineou C, Radcliffe PM, Olanow CW (1997) L-(-)-Desmethylselegiline, a metabolite of selegiline [L-(-)-deprenyl], protects mesencephalic dopamine neurons from excitotoxicity in vitro. J Neurochem 68: 434–436

    Article  PubMed  CAS  Google Scholar 

  • O’Brien EM, Tipton K (1994) Biochemistry and mechanism of action of monoamine oxidases A and B. In: Lieberman A, Olanow W, Youdim MBH, Tipton K (eds) Monoamine oxidase inhibitors in neurological diseases. Marcel Dekker, New York Basel Hong Kong, pp 31–76

    Google Scholar 

  • Olanow CW, Hauser RA, Gauger L, Malapira T, Koller W, Hubble J, Bushenbark K, Lilienfeld D, Esterlitz J (1995) The effect of deprenyl and levodopa on the progression of Parkinson’s disease. Ann Neurol 38: 771–777

    Article  PubMed  CAS  Google Scholar 

  • Parkinson Study Group (1996) Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP subjects not requiring levodopa. Ann Neurol 39: 29–36

    Article  Google Scholar 

  • Paterson IA, Juorio AV, Boulton AA (1990) 2-Phenylethylamine: a modulator of catecholamine transmission in the mammalian central nervous system? J Neurochem 55: 1827–1837

    Article  PubMed  CAS  Google Scholar 

  • Pattichis K, Louca LL, Clow A, Glover V (1995) Effects of pergolide, (-)-deprenyl and thioridazine on soluble SOD, catalase and glutathione peroxidase in rat striata. Med Sci Res 23: 733–735

    CAS  Google Scholar 

  • Przuntek H (1994) Clinical aspects of neuroprotection in Parkinson’s disease. J Neural Transm [Suppl] 43: 163–169

    CAS  Google Scholar 

  • Reynoids GP, Riederer P, Sandler M, Jellinger K, Seemann D (1978) Amphetamine and phe-nylethylamine in post-mortem Parkinson’s brain after (-)deprenyl administration. J Neural Transm 43: 271–277

    Article  Google Scholar 

  • Riederer P, Youdim MBH (1986) Monoamine oxidase activity and monoamine metabolism in brains of parkinsonian patients treated with L-deprenyl. J Neurochem 46: 1359–1365

    Article  PubMed  CAS  Google Scholar 

  • Riederer P, Youdim MBH, Rausch WD, Birkmayer W, Jellinger K, Seemann D (1978) On the mode of action of L-deprenyl in the human central nervous system. J Neural Transm 43: 217–226

    Article  PubMed  CAS  Google Scholar 

  • Riederer P, Jellinger K, Seemann D (1984) Monoamine oxidase and parkinsonism. In: Tipton K, Dostert P, Strolin-Benedetti M (eds) Monoamine oxidase and disease. Academic Press, London Orlando San Diego, pp 404–415

    Google Scholar 

  • Roy E, Bedard PJ (1993) Deprenyl increases survival of rat foetal nigral neurones in culture. Neuro Report 4: 1183–1186

    CAS  Google Scholar 

  • Salo PT, Tatton WG (1992) Deprenyl reduces the death of motoneurons caused by axoto-my. J Neurosci Res 31: 394–400

    Article  PubMed  CAS  Google Scholar 

  • Semkova I, Wolz P, Schilling M, Kriegistein J (1996) Selegiline enhances NGF synthesis and protects central nervous system (CNS) neurons from excitotoxic and ischemic damage. Eur J Pharmacol 315: 19–30

    Article  PubMed  CAS  Google Scholar 

  • Squires RF (1972) Multiple forms of monoamine oxidase in intact mitochondria as characterized by selective inhibitors and thermal stability: a comparison of eight mammalian species. Adv Biochem Psychopharmacol 5: 355–370

    PubMed  CAS  Google Scholar 

  • Szelenyi I (1993) Inhibitors of monoamine oxidase B. Pharmacology and clinical use in neurodegenerative disorders. Birkhäuser, Basel Boston Berlin

    Google Scholar 

  • Tatton WG, Greenwood CE (1991) Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism. J Neurosci Res 30: 666–672

    Article  PubMed  CAS  Google Scholar 

  • Tatton WG, Wadia JS, Ju WYH, Chalmers-Redman RME, Tatton NA (1996) (-)-Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase. J Neural Transm [Suppl] 48: 45–59

    CAS  Google Scholar 

  • Taylor KM, Snyder SH (1974) Amphetamine: differentiation by D and L isomers of behaviour involving brain norepinephrine or dopamine. Science 168: 1487–1489

    Article  Google Scholar 

  • The Parkinson Study Group (1989) Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 321: 1364–1371

    Article  Google Scholar 

  • The Parkinson Study Group (1993) Effects of Tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 328: 176–184

    Article  Google Scholar 

  • The Parkinson Study Group (1996) Effect of lazabemide on the progression of disability in early Parkinson’s disease. Ann Neurol 40: 99–107

    Article  Google Scholar 

  • Wu R-M, Murphy DL, Chiueh CC (1995) Neuronal protective and rescue effects of deprenyl against MPP+ dopaminergic toxicity. J Neural Transm [Gen Sect] 100: 53–61

    Article  CAS  Google Scholar 

  • Yasar S, Goldberg, JP, Goldberg SR (1996) Are metabolites of L-deprenyl (selegiline) useful or harmful? Indications from preclinical research. J Neural Transm [Suppl] 48: 61–73

    CAS  Google Scholar 

  • Youdim MBH, Collins GGS, Sandler M, Pare CBM, Bevan-Jones AB, Nicholson WJ (1972) Human brain monoamine oxidase: multiple forms and selective inhibition. Nature 236: 225–228

    Article  PubMed  CAS  Google Scholar 

  • Youdim MBH, Finberg JPM, Tipton KF (1988) Monoamine oxidase. In: Trendelenburg U, Weiner N (eds) Catecholamines I. Springer, Berlin Heidelberg New York Tokyo, pp 119–192 (Handb Exp Pharmacol 90/I)

    Chapter  Google Scholar 

  • Yu PH, Davis BA, Fang J, Boulton AA (1994) Neuroprotective effects of some monoamine oxidase-B inhibitors against DSP-4-induced noradrenaline depletion in the mouse hippocampus. J Neurochem 63: 1820–1828

    Article  PubMed  CAS  Google Scholar 

  • Zhang X, Zuo DM, Davis BA, Boulton AA, Yu PH (1996) Immunohistochemical evidence of neuroprotection by R(-)-deprenyl and N-(2-hexyl)-N-methylpropargylamine on DSP-4-induced degeneration of rat brain noradrenergic axons and terminale. J Neurosci Res 43: 482–489

    Article  PubMed  CAS  Google Scholar 

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Gerlach, M., Riederer, P. (1999). Neurobiochemie und Wirkmechanismus von Selegilin. In: Riederer, P., Laux, G., Pöldinger, W. (eds) Neuro-Psychopharmaka Ein Therapie-Handbuch. Springer, Vienna. https://doi.org/10.1007/978-3-7091-6400-6_21

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