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
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
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
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
Bentué-Ferrer D, Menard G, Allain H (1996) Monoamine oxidase B inhibitors. Current status and future potential. CNS Drugs 6: 217–236
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
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
Bieck PR (1989) Hypertensive Krisen unter reversiblen Hemmstoffen der Monoaminoxidase? Ergebnisse von Tyramin-Interaktionsstudien. Psychiatr Prax 16 [Sonderheft]: 25–31
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
Blackwell B, Marley E, Price J, Taylor D (1967) Hypertensive interactions between monoamine inhibitors and foodstuffs. Br J Psychiatry 113: 349–365
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Gerlach M, Riederer P, Youdim MBH (1992) The molecular pharmacology of L-deprenyl. Eur J Pharmacol [Mol Pharmacol Sect] 226: 97–108
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)
Gerlach M, Youdim MBH, Riederer P (1996b) Pharmacology of selegiline. Neurology 47[Suppl 3]: S137–S145
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
Giulian D, Vaca K, Corpuz M (1993) Brain glia release factors with opposing actions upon neuronal survival. J Neurosci 13: 29–37
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
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
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
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
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
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
Huie RE, Padmaja S (1993) The reaction rate of nitric oxide with superoxide. Free Rad Res Commun 18: 195–199
Johnston JP (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 17: 1285–1297
Knoll J (1987) R-(-)-deprenyl (Selegiline, Movergan®) facilitates the activity of the nigrostriatal dopaminergic neuron. J Neural Transm 25 [Suppl]: 45–66
Knoll J (1988) The striatal dopamine dependency of life span in male rats, longevity study with (-)deprenyl. Mech Ageing Dev 46: 237–262
Knoll J, Magyar K (1972) Some puzzling effects of monoamine oxidase inhibitors. Adv Biochem Psychopharmacol 5: 393–408
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
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
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
Lindsay RM, Wiegand SJ, Altar CA, Distefano PS (1994) Neurotrophic factors: from molecule to man. Trends Neurol Sci 17: 182–190
Magyar K (1994) Behaviour of (-)-deprenyl and its analogues. J Neural Transm [Suppl] 41:167–175
Magyar K, Tothfalusi L (1984) Pharmacokinetic aspects of deprenyl effects. Pol J Pharmacol Pharm 36: 373–384
Mcgeer PL, Mcgeer EG, Suzuki JS (1977) Aging and extrapyramidal function. Arch Neurol 34: 33–35
Mcgeer PL, Itagaki S’, Akiyama H, Mcgeer EG (1988) Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol 24: 574–576
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
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
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
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
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
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
Przuntek H (1994) Clinical aspects of neuroprotection in Parkinson’s disease. J Neural Transm [Suppl] 43: 163–169
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
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
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
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
Roy E, Bedard PJ (1993) Deprenyl increases survival of rat foetal nigral neurones in culture. Neuro Report 4: 1183–1186
Salo PT, Tatton WG (1992) Deprenyl reduces the death of motoneurons caused by axoto-my. J Neurosci Res 31: 394–400
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
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
Szelenyi I (1993) Inhibitors of monoamine oxidase B. Pharmacology and clinical use in neurodegenerative disorders. Birkhäuser, Basel Boston Berlin
Tatton WG, Greenwood CE (1991) Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism. J Neurosci Res 30: 666–672
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
Taylor KM, Snyder SH (1974) Amphetamine: differentiation by D and L isomers of behaviour involving brain norepinephrine or dopamine. Science 168: 1487–1489
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
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
The Parkinson Study Group (1996) Effect of lazabemide on the progression of disability in early Parkinson’s disease. Ann Neurol 40: 99–107
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
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
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
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)
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
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
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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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