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Open Access 01-05-2020 | Parkinson's Disease | Neurology and Preclinical Neurological Studies - Review Article

Selegiline: a molecule with innovative potential

Authors: Tamás Tábi, László Vécsei, Moussa B. Youdim, Peter Riederer, Éva Szökő

Published in: Journal of Neural Transmission | Issue 5/2020

Abstract

Monoamine oxidase B (MAO-B) inhibitors have an established role in the treatment of Parkinson’s disease as monotherapy or adjuvant to levodopa. Two major recognitions were required for their introduction into this therapeutic field. The first was the elucidation of the novel pharmacological properties of selegiline as a selective MAO-B inhibitor by Knoll and Magyar and the original idea of Riederer and Youdim, supported by Birkmayer, to explore its effect in parkinsonian patients with on–off phases. In the 1960s, MAO inhibitors were mainly studied as potential antidepressants, but Birkmayer found that combined use of levodopa and various MAO inhibitors improved akinesia in Parkinson’s disease. However, the serious side effects of the first non-selective MAO inhibitors prevented their further use. Later studies demonstrated that MAO-B, mainly located in glial cells, is important for dopamine metabolism in the brain. Recently, cell and molecular studies revealed interesting properties of selegiline opening new possibilities for neuroprotective mechanisms and a disease-modifying effect of MAO-B inhibitors.

Allain H, Pollak P, Neukirch HC (1993) Symptomatic effect of selegiline in de novo Parkinsonian patients. The French Selegiline Multicenter Trial. Mov Disord 8(Suppl 1):S36–40PubMedCrossRef

Amsterdam JD (2003) A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry 64(2):208–214PubMedCrossRef

Amsterdam JD, Bodkin JA (2006) Selegiline transdermal system in the prevention of relapse of major depressive disorder: a 52-week, double-blind, placebo-substitution, parallel-group clinical trial. J Clin Psychopharmacol 26(6):579–586. https://doi.org/10.1097/01.jcp.0000239794.37073.70 CrossRefPubMed

Azzaro AJ, Ziemniak J, Kemper E, Campbell BJ, VanDenBerg C (2007) Pharmacokinetics and absolute bioavailability of selegiline following treatment of healthy subjects with the selegiline transdermal system (6 mg/24 h): a comparison with oral selegiline capsules. J Clin Pharmacol 47(10):1256–1267. https://doi.org/10.1177/0091270007304779 CrossRefPubMed

Bartl J, Muller T, Grunblatt E, Gerlach M, Riederer P (2014) Chronic monoamine oxidase-B inhibitor treatment blocks monoamine oxidase-A enzyme activity. J Neural Transm (Vienna) 121(4):379–383. https://doi.org/10.1007/s00702-013-1120-z CrossRef

Bekesi G, Tulassay Z, Lengyel G, Schaff Z, Szombath D, Stark J, Marczell I, Nagy-Repas P, Adler I, Dinya E, Racz K, Magyar K (2012) The effect of selegiline on total scavenger capacity and liver fat content: a preliminary study in an animal model. J Neural Transm (Vienna) 119(1):25–30. https://doi.org/10.1007/s00702-011-0666-x CrossRef

Ben-Shlomo Y, Churchyard A, Head J, Hurwitz B, Overstall P, Ockelford J, Lees AJ (1998) Investigation by Parkinson’s Disease Research Group of United Kingdom into excess mortality seen with combined levodopa and selegiline treatment in patients with early, mild Parkinson’s disease: further results of randomised trial and confidential inquiry. BMJ 316(7139):1191–1196. https://doi.org/10.1136/bmj.316.7139.1191 CrossRefPubMedPubMedCentral

Biberman R, Neumann R, Katzir I, Gerber Y (2003) A randomized controlled trial of oral selegiline plus nicotine skin patch compared with placebo plus nicotine skin patch for smoking cessation. Addiction 98(10):1403–1407PubMedCrossRef

Binde CD, Tvete IF, Gasemyr J, Natvig B, Klemp M (2018) A multiple treatment comparison meta-analysis of monoamine oxidase type B inhibitors for Parkinson’s disease. Br J Clin Pharmacol 84(9):1917–1927. https://doi.org/10.1111/bcp.13651 CrossRefPubMedPubMedCentral

Birkmayer W (1983) Deprenyl (selegiline) in the treatment of Parkinson’s disease. Acta Neurol Scand Suppl 95:103–105PubMedCrossRef

Birkmayer W, Hornykiewicz O (1962) The l-dihydroxyphenylalanine (l-DOPA) effect in Parkinson’s syndrome in man: on the pathogenesis and treatment of Parkinson akinesis. Arch Psychiatr Nervenkr Z Gesamte Neurol Psychiatr 203:560–574PubMedCrossRef

Birkmayer W, Riederer P, Youdim MB, Linauer W (1975) The potentiation of the anti akinetic effect after l-dopa treatment by an inhibitor of MAO-B, Deprenil. J Neural Transm 36(3–4):303–326PubMedCrossRef

Birkmayer W, Riederer P, Ambrozi L, Youdim MB (1977) Implications of combined treatment with ‘Madopar’ and l-deprenil in Parkinson’s disease. A long-term study. Lancet 1(8009):439–443PubMedCrossRef

Birkmayer W, Knoll J, Riederer P, Youdim MB, Hars V, Marton J (1985) Increased life expectancy resulting from addition of l-deprenyl to Madopar treatment in Parkinson’s disease: a longterm study. J Neural Transm 64(2):113–127PubMedCrossRef

Birks J, Flicker L (2003) Selegiline for Alzheimer’s disease. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.cd000442 CrossRefPubMed

Blob LF, Sharoky M, Campbell BJ, Kemper EM, Gilmor MG, VanDenberg CM, Azzaro AJ (2007) Effects of a tyramine-enriched meal on blood pressure response in healthy male volunteers treated with selegiline transdermal system 6 mg/24 h. CNS Spectr 12(1):25–34PubMedCrossRef

Bodkin JA, Amsterdam JD (2002) Transdermal selegiline in major depression: a double-blind, placebo-controlled, parallel-group study in outpatients. Am J Psychiatry 159(11):1869–1875. https://doi.org/10.1176/appi.ajp.159.11.1869 CrossRefPubMed

Brannan T, Yahr MD (1995) Comparative study of selegiline plus l-dopa-carbidopa versus l-dopa-carbidopa alone in the treatment of Parkinson’s disease. Ann Neurol 37(1):95–98. https://doi.org/10.1002/ana.410370117 CrossRefPubMed

Burke WJ, Roccaforte WH, Wengel SP, Bayer BL, Ranno AE, Willcockson NK (1993) l-Deprenyl in the treatment of mild dementia of the Alzheimer type: results of a 15-month trial. J Am Geriatr Soc 41(11):1219–1225PubMedCrossRef

Campi N, Todeschini GP, Scarzella L (1990) Selegiline versus l-acetylcarnitine in the treatment of Alzheimer-type dementia. Clin Ther 12(4):306–314PubMed

Clarke A, Brewer F, Johnson ES, Mallard N, Hartig F, Taylor S, Corn TH (2003a) A new formulation of selegiline: improved bioavailability and selectivity for MAO-B inhibition. J Neural Transm (Vienna) 110(11):1241–1255. https://doi.org/10.1007/s00702-003-0036-4 CrossRef

Clarke A, Johnson ES, Mallard N, Corn TH, Johnston A, Boyce M, Warrington S, MacMahon DG (2003b) A new low-dose formulation of selegiline: clinical efficacy, patient preference and selectivity for MAO-B inhibition. J Neural Transm (Vienna) 110(11):1257–1271. https://doi.org/10.1007/s00702-003-0042-6 CrossRef

Collins GG, Sandler M, Williams ED, Youdim MB (1970) Multiple forms of human brain mitochondrial monoamine oxidase. Nature 225(5235):817–820PubMedCrossRef

DelBello MP, Hochadel TJ, Portland KB, Azzaro AJ, Katic A, Khan A, Emslie G (2014) A double-blind, placebo-controlled study of selegiline transdermal system in depressed adolescents. J Child Adolesc Psychopharmacol 24(6):311–317. https://doi.org/10.1089/cap.2013.0138 CrossRefPubMedPubMedCentral

Dezsi L, Vecsei L (2014) Safinamide for the treatment of Parkinson’s disease. Expert Opin Investig Drugs 23(5):729–742. https://doi.org/10.1517/13543784.2014.897694 CrossRefPubMed

Dezsi L, Vecsei L (2017) Monoamine oxidase B inhibitors in Parkinson’s disease. CNS Neurol Disord: Drug Targets 16(4):425–439. https://doi.org/10.2174/1871527316666170124165222 CrossRef

Elkashef A, Fudala PJ, Gorgon L, Li SH, Kahn R, Chiang N, Vocci F, Collins J, Jones K, Boardman K, Sather M (2006) Double-blind, placebo-controlled trial of selegiline transdermal system (STS) for the treatment of cocaine dependence. Drug Alcohol Depend 85(3):191–197. https://doi.org/10.1016/j.drugalcdep.2006.04.010 CrossRefPubMed

Elmer LW (2013) Rasagiline adjunct therapy in patients with Parkinson’s disease: post hoc analyses of the PRESTO and LARGO trials. Parkinsonism Relat Disord 19(11):930–936. https://doi.org/10.1016/j.parkreldis.2013.06.001 CrossRefPubMed

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(1–2):105–110PubMedCrossRef

Fabbrini G, Abbruzzese G, Marconi S, Zappia M (2012) Selegiline: a reappraisal of its role in Parkinson disease. Clin Neuropharmacol 35(3):134–140. https://doi.org/10.1097/WNF.0b013e318255838b CrossRefPubMed

Feiger AD, Rickels K, Rynn MA, Zimbroff DL, Robinson DS (2006) Selegiline transdermal system for the treatment of major depressive disorder: an 8-week, double-blind, placebo-controlled, flexible-dose titration trial. J Clin Psychiatry 67(9):1354–1361PubMedCrossRef

Filip V, Kolibas E (1999) Selegiline in the treatment of Alzheimer’s disease: a long-term randomized placebo-controlled trial. Czech and Slovak Senile Dementia of Alzheimer Type Study Group. J Psychiatry Neurosci 24(3):234–243PubMedPubMedCentral

Finali G, Piccirilli M, Oliani C, Piccinin GL (1992) Alzheimer-type dementia and verbal memory performances: influence of selegiline therapy. Ital J Neurol Sci 13(2):141–148PubMedCrossRef

Finberg JP, Gillman K (2011) Selective inhibitors of monoamine oxidase type B and the “cheese effect”. Int Rev Neurobiol 100:169–190. https://doi.org/10.1016/b978-0-12-386467-3.00009-1 CrossRefPubMed

Finberg JP, Youdim MB (1983) Selective MAO A and B inhibitors: their mechanism of action and pharmacology. Neuropharmacology 22(3 Spec No):441–446PubMedCrossRef

Fowler JS, Logan J, Volkow ND, Shumay E, McCall-Perez F, Jayne M, Wang GJ, Alexoff DL, Apelskog-Torres K, Hubbard B, Carter P, King P, Fahn S, Gilmor M, Telang F, Shea C, Xu Y, Muench L (2015) Evidence that formulations of the selective MAO-B inhibitor, selegiline, which bypass first-pass metabolism, also inhibit MAO-A in the human brain. Neuropsychopharmacology 40(3):650–657. https://doi.org/10.1038/npp.2014.214 CrossRefPubMed

Friedhoff AJ (1990) Deprenyl and the progression of Parkinson’s disease. Science 249(4966):303–304CrossRef

Gaur S, Gross ME, Liao CP, Qian B, Shih JC (2019) Effect of Monoamine oxidase A (MAOA) inhibitors on androgen-sensitive and castration-resistant prostate cancer cells. Prostate 79(6):667–677. https://doi.org/10.1002/pros.23774 CrossRefPubMedPubMedCentral

Gerlach M, Youdim MB, Riederer P (1996) Pharmacology of selegiline. Neurology 47(6 Suppl 3):S137–145PubMedCrossRef

Glover V, Sandler M, Owen F, Riley GJ (1977) Dopamine is a monoamine oxidase B substrate in man. Nature 265(5589):80–81PubMedCrossRef

Hauser RA, Lew MF, Hurtig HI, Ondo WG, Wojcieszek J, Fitzer-Attas CJ (2009) Long-term outcome of early versus delayed rasagiline treatment in early Parkinson’s disease. Mov Disord 24(4):564–573. https://doi.org/10.1002/mds.22402 CrossRefPubMed

Hauser RA, Li R, Perez A, Ren X, Weintraub D, Elm J, Goudreau JL, Morgan JC, Fang JY, Aminoff MJ, Christine CW, Dhall R, Umeh CC, Boyd JT, Stover N, Leehey M, Zweig RM, Nicholas AP, Bodis-Wollner I, Willis A, Kieburtz K, Tilley BC (2017) Longer duration of MAO-b inhibitor exposure is associated with less clinical decline in Parkinson’s disease: an analysis of NET-PD LS1. J Parkinsons Dis 7(1):117–127. https://doi.org/10.3233/jpd-160965 CrossRefPubMed

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

Ives NJ, Stowe RL, Marro J, Counsell C, Macleod A, Clarke CE, Gray R, Wheatley K (2004) Monoamine oxidase type B inhibitors in early Parkinson’s disease: meta-analysis of 17 randomised trials involving 3525 patients. BMJ 329(7466):593. https://doi.org/10.1136/bmj.38184.606169.AE CrossRefPubMedPubMedCentral

Johnston JP (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem Pharmacol 17(7):1285–1297PubMedCrossRef

Kahn R, Gorgon L, Jones K, McSherry F, Glover ED, Anthenelli RM, Jackson T, Williams J, Murtaugh C, Montoya I, Yu E, Elkashef A (2012) Selegiline transdermal system (STS) as an aid for smoking cessation. Nicotine Tob Res 14(3):377–382. https://doi.org/10.1093/ntr/ntr143 CrossRefPubMed

Killen JD, Fortmann SP, Murphy GM Jr, Hayward C, Fong D, Lowenthal K, Bryson SW, Killen DT, Schatzberg AF (2010) Failure to improve cigarette smoking abstinence with transdermal selegiline + cognitive behavior therapy. Addiction 105(9):1660–1668. https://doi.org/10.1111/j.1360-0443.2010.03020.x CrossRefPubMedPubMedCentral

Knoll J (1979) Selective inhibitors of MAO-B with different pharmacological profiles. In: Magyar K (ed) Monoamine oxidases and their selective inhibition, vol IV. Pergamon Press, Budapest, pp 23–36

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

Knoll J, Ecseri Z, Kelemen K, Nievel J, Knoll B (1965) Phenylisopropylmethylpropinylamine (E-250), a new spectrum psychic energizer. Arch Int Pharmacodyn Ther 155(1):154–164PubMed

Knoll J, Ecsery Z, Magyar K, Satory E (1978) Novel (−)deprenyl-derived selective inhibitors of B-type monoamine oxidase. The relation of structure to their action. Biochem Pharmacol 27(13):1739–1747. https://doi.org/10.1016/0006-2952(78)90550-6 CrossRefPubMed

Konradi C, Kornhuber J, Froelich L, Fritze J, Heinsen H, Beckmann H, Schulz E, Riederer P (1989) Demonstration of monoamine oxidase-A and -B in the human brainstem by a histochemical technique. Neuroscience 33(2):383–400PubMedCrossRef

Larsen JP, Boas J, Erdal JE (1999) Does selegiline modify the progression of early Parkinson’s disease? Results from a 5-year study. The Norwegian–Danish Study Group. Eur J Neurol 6(5):539–547CrossRefPubMed

Lees AJ (1995) Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson’s disease Parkinson’s Disease Research Group of the United Kingdom. BMJ 311(7020):1602–1607. https://doi.org/10.1136/bmj.311.7020.1602 CrossRefPubMedPubMedCentral

Lighezan R, Sturza A, Duicu OM, Ceausu RA, Vaduva A, Gaspar M, Feier H, Vaida M, Ivan V, Lighezan D, Muntean DM, Mornos C (2016) Monoamine oxidase inhibition improves vascular function in mammary arteries from nondiabetic and diabetic patients with coronary heart disease. Can J Physiol Pharmacol 94(10):1040–1047. https://doi.org/10.1139/cjpp-2015-0580 CrossRefPubMed

Macleod AD, Counsell CE, Ives N, Stowe R (2005) Monoamine oxidase B inhibitors for early Parkinson’s disease. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.cd004898.pub2 CrossRefPubMedPubMedCentral

Magyar K, Vizi ES, Ecseri Z, Knoll J (1967) Comparative pharmacological analysis of the optical isomers of phenyl-isopropyl-methyl-propinylamine (E-250). Acta Physiol Acad Sci Hung 32(4):377–387PubMed

Magyar K, Ecseri Z, Bernáth G, Sátory É, Knoll J (1979) Sturcture-activity relationship of selective inhibitors of MAO-B. In: Magyar K (ed) Monoamine oxidases and their selective inhibition. Pergamon Press, Budapest, pp 11–21

Magyar K, Palfi M, Tabi T, Kalasz H, Szende B, Szoko E (2004) Pharmacological aspects of (−)-deprenyl. Curr Med Chem 11(15):2017–2031PubMedCrossRef

Magyar K, Palfi M, Jenei V, Szoko E (2006) Deprenyl: from chemical synthesis to neuroprotection. J Neural Transm Suppl 71:143–156

Magyar K, Szende B, Jenei V, Tabi T, Palfi M, Szoko E (2010) R-Deprenyl: pharmacological spectrum of its activity. Neurochem Res 35(12):1922–1932. https://doi.org/10.1007/s11064-010-0238-8 CrossRefPubMed

Mally J, Kovacs AB, Stone TW (1995) Delayed development of symptomatic improvement by (−)-deprenyl in Parkinson’s disease. J Neurol Sci 134(1–2):143–145PubMedCrossRef

Mangoni A, Grassi MP, Frattola L, Piolti R, Bassi S, Motta A, Marcone A, Smirne S (1991) Effects of a MAO-B inhibitor in the treatment of Alzheimer disease. Eur Neurol 31(2):100–107. https://doi.org/10.1159/000116655 CrossRefPubMed

Mann JJ, Aarons SF, Wilner PJ, Keilp JG, Sweeney JA, Pearlstein T, Frances AJ, Kocsis JH, Brown RP (1989) A controlled study of the antidepressant efficacy and side effects of (−)-deprenyl. A selective monoamine oxidase inhibitor. Arch Gen Psychiatry 46(1):45–50PubMedCrossRef

Marsili L, Marconi R, Colosimo C (2017) Treatment strategies in early Parkinson’s Disease. Int Rev Neurobiol 132:345–360. https://doi.org/10.1016/bs.irn.2017.01.002 CrossRefPubMed

Maruyama W, Naoi M (2013) “70th Birthday Professor Riederer” induction of glial cell line-derived and brain-derived neurotrophic factors by rasagiline and (−)deprenyl: a way to a disease-modifying therapy? J Neural Transm (Vienna) 120(1):83–89. https://doi.org/10.1007/s00702-012-0876-x CrossRef

Mawhinney M, Cole D, Azzaro AJ (2003) Daily transdermal administration of selegiline to guinea-pigs preferentially inhibits monoamine oxidase activity in brain when compared with intestinal and hepatic tissues. J Pharm Pharmacol 55(1):27–34. https://doi.org/10.1211/002235702478 CrossRefPubMed

Mizuno Y, Kondo T, Kuno S, Nomoto M, Yanagisawa N (2010) Early addition of selegiline to l-Dopa treatment is beneficial for patients with Parkinson disease. Clin Neuropharmacol 33(1):1–4. https://doi.org/10.1097/WNF.0b013e3181bbf45c CrossRefPubMed

Mizuno Y, Hattori N, Kondo T, Nomoto M, Origasa H, Takahashi R, Yamamoto M, Yanagisawa N (2017) A randomized double-blind placebo-controlled phase III trial of selegiline monotherapy for early parkinson disease. Clin Neuropharmacol 40(5):201–207. https://doi.org/10.1097/wnf.0000000000000239 CrossRefPubMedPubMedCentral

Monteverde A, Gnemmi P, Rossi F, Monteverde A, Finali GC (1990) Selegiline in the treatment of mild to moderate Alzheimer-type dementia. Clin Ther 12(4):315–322PubMed

Muller T, Mohr JD (2019) Pharmacokinetics of monoamine oxidase B inhibitors in Parkinson’s disease: current status. Expert Opin Drug Metab Toxicol 15(5):429–435. https://doi.org/10.1080/17425255.2019.1607292 CrossRefPubMed

Myllyla VV, Sotaniemi KA, Vuorinen JA, Heinonen EH (1991) Selegiline as a primary treatment of Parkinson’s disease. Acta Neurol Scand Suppl 136:70–72PubMedCrossRef

Myllyla VV, Sotaniemi KA, Vuorinen JA, Heinonen EH (1993) Selegiline in de novo parkinsonian patients: the Finnish study. Mov Disord 8(Suppl 1):S41–44PubMedCrossRef

Myllyla VV, Sotaniemi KA, Hakulinen P, Maki-Ikola O, Heinonen EH (1997) Selegiline as the primary treatment of Parkinson’s disease—a long-term double-blind study. Acta Neurol Scand 95(4):211–218PubMedCrossRef

Nagy CT, Koncsos G, Varga ZV, Baranyai T, Tuza S, Kassai F, Ernyey AJ, Gyertyan I, Kiraly K, Olah A, Radovits T, Merkely B, Bukosza N, Szenasi G, Hamar P, Mathe D, Szigeti K, Pelyhe C, Jelemensky M, Onodi Z, Helyes Z, Schulz R, Giricz Z, Ferdinandy P (2018) Selegiline reduces adiposity induced by high-fat, high-sucrose diet in male rats. Br J Pharmacol 175(18):3713–3726. https://doi.org/10.1111/bph.14437 CrossRefPubMedPubMedCentral

Naoi M, Maruyama W (2010) Monoamine oxidase inhibitors as neuroprotective agents in age-dependent neurodegenerative disorders. Curr Pharm Des 16(25):2799–2817PubMedCrossRef

Nickel B, Szelenyi I, Schulze G (1994) Evaluation of physical dependence liability of l-deprenyl (selegiline) in animals. Clin Pharmacol Ther 56(6 Pt 2):757–767. https://doi.org/10.1038/clpt.1994.206 CrossRefPubMed

O’Carroll AM, Fowler CJ, Phillips JP, Tobbia I, Tipton KF (1983) The deamination of dopamine by human brain monoamine oxidase. Specificity for the two enzyme forms in seven brain regions. Naunyn Schmiedebergs Arch Pharmacol 322(3):198–202PubMedCrossRef

Olanow CW (2009) Can we achieve neuroprotection with currently available anti-parkinsonian interventions? Neurology 72(7 Suppl):S59–64. https://doi.org/10.1212/WNL.0b013e318199068b CrossRefPubMed

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(5):771–777. https://doi.org/10.1002/ana.410380512 CrossRefPubMed

Olanow CW, Myllyla VV, Sotaniemi KA, Larsen JP, Palhagen S, Przuntek H, Heinonen EH, Kilkku O, Lammintausta R, Maki-Ikola O, Rinne UK (1998) Effect of selegiline on mortality in patients with Parkinson’s disease: a meta-analysis. Neurology 51(3):825–830PubMedCrossRef

Olanow CW, Rascol O, Hauser R, Feigin PD, Jankovic J, Lang A, Langston W, Melamed E, Poewe W, Stocchi F, Tolosa E (2009) A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N Engl J Med 361(13):1268–1278. https://doi.org/10.1056/NEJMoa0809335 CrossRefPubMed

Palhagen S, Heinonen EH, Hagglund J, Kaugesaar T, Kontants H, Maki-Ikola O, Palm R, Turunen J (1998) Selegiline delays the onset of disability in de novo parkinsonian patients. Swedish Parkinson Study Group. Neurology 51(2):520–525PubMedCrossRef

Palhagen S, Heinonen E, Hagglund J, Kaugesaar T, Maki-Ikola O, Palm R (2006) Selegiline slows the progression of the symptoms of Parkinson disease. Neurology 66(8):1200–1206. https://doi.org/10.1212/01.wnl.0000204007.46190.54 CrossRefPubMed

Parkinson Study Group (1989) Effect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 321(20):1364–1371. https://doi.org/10.1056/nejm198911163212004 CrossRef

Parkinson Study Group (1993) Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 328(3):176–183. https://doi.org/10.1056/nejm199301213280305 CrossRef

Parkinson Study Group (1996) Impact of deprenyl and tocopherol treatment on Parkinson’s disease in DATATOP subjects not requiring levodopa. Parkinson Study Group. Ann Neurol 39(1):29–36. https://doi.org/10.1002/ana.410390106 CrossRef

Parkinson Study Group (2002) A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Arch Neurol 59(12):1937–1943CrossRef

Parkinson Study Group (2005) A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Arch Neurol 62(2):241–248. https://doi.org/10.1001/archneur.62.2.241 CrossRef

Przuntek H, Conrad B, Dichgans J, Kraus PH, Krauseneck P, Pergande G, Rinne U, Schimrigk K, Schnitker J, Vogel HP (1999) SELEDO: a 5-year long-term trial on the effect of selegiline in early Parkinsonian patients treated with levodopa. Eur J Neurol 6(2):141–150PubMedCrossRef

Qin F, Shite J, Mao W, Liang CS (2003) Selegiline attenuates cardiac oxidative stress and apoptosis in heart failure: association with improvement of cardiac function. Eur J Pharmacol 461(2–3):149–158PubMedCrossRef

Rascol O, Brooks DJ, Melamed E, Oertel W, Poewe W, Stocchi F, Tolosa E (2005) Rasagiline as an adjunct to levodopa in patients with Parkinson’s disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial. Lancet 365(9463):947–954. https://doi.org/10.1016/s0140-6736(05)71083-7 CrossRefPubMed

Reynolds GP, Riederer P, Sandler M, Jellinger K, Seemann D (1978) Amphetamine and 2-phenylethylamine in post-mortem Parkinsonian brain after (−)deprenyl administration. J Neural Transm 43(3–4):271–277PubMedCrossRef

Riederer P, Laux G (2011) MAO-inhibitors in Parkinson’s disease. Exp Neurobiol 20(1):1–17. https://doi.org/10.5607/en.2011.20.1.1 CrossRefPubMedPubMedCentral

Riederer P, Muller T (2018) Monoamine oxidase-B inhibitors in the treatment of Parkinson’s disease: clinical-pharmacological aspects. J Neural Transm (Vienna) 125(11):1751–1757. https://doi.org/10.1007/s00702-018-1876-2 CrossRef

Riederer P, Youdim MB (1986) Monoamine oxidase activity and monoamine metabolism in brains of parkinsonian patients treated with l-deprenyl. J Neurochem 46(5):1359–1365PubMedCrossRef

Riederer P, Youdim MB, 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(3–4):217–226PubMedCrossRef

Riederer P, Jellinger K, Seemann D (1984) Monoamine oxidase and parkinsonism. In: Tipton KF, Dostert P, Strolin-Benedetti M (eds) Monoamine oxidase and disease. Academic Press, London, pp 403–415

Riederer P, Konradi C, Schay V, Kienzl E, Birkmayer G, Danielczyk W, Sofic E, Youdim MB (1987) Localization of MAO-A and MAO-B in human brain: a step in understanding the therapeutic action of l-deprenyl. Adv Neurol 45:111–118PubMed

Ryu I, Ryu MJ, Han J, Kim SJ, Lee MJ, Ju X, Yoo BH, Lee YL, Jang Y, Song IC, Chung W, Oh E, Heo JY, Kweon GR (2018) l-Deprenyl exerts cytotoxicity towards acute myeloid leukemia through inhibition of mitochondrial respiration. Oncol Rep 40(6):3869–3878. https://doi.org/10.3892/or.2018.6753 CrossRefPubMed

Schulzer M (1997) Treatment of Parkinson’s disease: disagreements. Ann Neurol 41(6):833–834. https://doi.org/10.1002/ana.410410622 CrossRefPubMed

Shih JC (2018) Monoamine oxidase isoenzymes: genes, functions and targets for behavior and cancer therapy. J Neural Transm (Vienna) 125(11):1553–1566. https://doi.org/10.1007/s00702-018-1927-8 CrossRef

Shin HS (1997) Metabolism of selegiline in humans. Identification, excretion, and stereochemistry of urine metabolites. Drug Metab Dispos 25(6):657–662PubMed

Shoulson I (1992) An interim report of the effect of selegiline (l-deprenyl) on the progression of disability in early Parkinson’s disease. The Parkinson Study Group. Eur Neurol 32(Suppl 1):46–53. https://doi.org/10.1159/000116869 CrossRefPubMed

Shoulson I, Oakes D, Fahn S, Lang A, Langston JW, LeWitt P, Olanow CW, Penney JB, Tanner C, Kieburtz K, Rudolph A (2002) Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson’s disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann Neurol 51(5):604–612. https://doi.org/10.1002/ana.10191 CrossRefPubMed

Stern GM, Lees AJ, Hardie RJ, Sandler M (1983) Clinical and pharmacological problems of deprenyl (selegiline) treatment in Parkinson’s disease. Acta Neurol Scand Suppl 95:113–116PubMedCrossRef

Sturza A, Duicu OM, Vaduva A, Danila MD, Noveanu L, Varro A, Muntean DM (2015) Monoamine oxidases are novel sources of cardiovascular oxidative stress in experimental diabetes. Can J Physiol Pharmacol 93(7):555–561. https://doi.org/10.1139/cjpp-2014-0544 CrossRefPubMed

Sunderland T, Cohen RM, Molchan S, Lawlor BA, Mellow AM, Newhouse PA, Tariot PN, Mueller EA, Murphy DL (1994) High-dose selegiline in treatment-resistant older depressive patients. Arch Gen Psychiatry 51(8):607–615PubMedCrossRef

Szende B, Magyar K, Szegedi Z (2000) Apoptotic and antiapoptotic effect of (−)deprenyl and (−)-desmethyl–deprenyl on human cell lines. Neurobiology (Bp) 8(3–4):249–255

Szende B, Bokonyi G, Bocsi J, Keri G, Timar F, Magyar K (2001) Anti-apoptotic and apoptotic action of (−)-deprenyl and its metabolites. J Neural Transm (Vienna) 108(1):25–33. https://doi.org/10.1007/s007020170094 CrossRef

Szoko E, Kalasz H, Magyar K (1999) Biotransformation of deprenyl enantiomers. Eur J Drug Metab Pharmacokinet 24(4):315–319PubMedCrossRef

Szoko E, Tabi T, Riederer P, Vecsei L, Magyar K (2018) Pharmacological aspects of the neuroprotective effects of irreversible MAO-B inhibitors, selegiline and rasagiline. Parkinson’s disease. J Neural Transm (Vienna) 125(11):1735–1749. https://doi.org/10.1007/s00702-018-1853-9 CrossRef

Tabi T, Magyar K, Szoko E (2003) Chiral characterization of deprenyl-N-oxide and other deprenyl metabolites by capillary electrophoresis using a dual cyclodextrin system in rat urine. Electrophoresis 24(15):2665–2673. https://doi.org/10.1002/elps.200305468 CrossRefPubMed

Tabi T, Szoko E, Vecsei L, Magyar K (2013) The pharmacokinetic evaluation of selegiline ODT for the treatment of Parkinson’s disease. Expert Opin Drug Metab Toxicol 9(5):629–636. https://doi.org/10.1517/17425255.2013.781152 CrossRefPubMed

Takahashi M, Yuasa R, Imai T, Tachibana H, Yorifuji S, Nakamura Y, Ogawa N (1994) Selegiline (l-deprenyl) and l-dopa treatment of Parkinson’s disease: a double-blind trial. Intern Med 33(9):517–524PubMedCrossRef

Tariot PN, Sunderland T, Weingartner H, Murphy DL, Welkowitz JA, Thompson K, Cohen RM (1987) Cognitive effects of l-deprenyl in Alzheimer’s disease. Psychopharmacology 91(4):489–495PubMedCrossRef

Teo KC, Ho SL (2013) Monoamine oxidase-B (MAO-B) inhibitors: implications for disease-modification in Parkinson’s disease. Transl Neurodegener 2(1):19. https://doi.org/10.1186/2047-9158-2-19 CrossRefPubMedPubMedCentral

Tetrud JW, Langston JW (1989) The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. Science 245(4917):519–522PubMedCrossRef

Tharakan B, Whaley JG, Hunter FA, Smythe WR, Childs EW (2010) (−)-Deprenyl inhibits vascular hyperpermeability after hemorrhagic shock. Shock 33(1):56–63. https://doi.org/10.1097/SHK.0b013e3181a7fb7c CrossRefPubMed

Unzeta M, Esteban G, Bolea I, Fogel WA, Ramsay RR, Youdim MB, Tipton KF, Marco-Contelles J (2016) Multi-target directed donepezil-like ligands for Alzheimer’s disease. Front Neurosci 10:205. https://doi.org/10.3389/fnins.2016.00205 CrossRefPubMedPubMedCentral

Varga E, Tringer L (1967) Clinical trial of a new type promptly acting psychoenergetic agent (phenyl-isopropyl-methylpropionyl-HCl, “E-250”). Acta Med Acad Sci Hung 23(3):289–295PubMed

Weinreb O, Amit T, Bar-Am O, Youdim MB (2010) Rasagiline: a novel anti-Parkinsonian monoamine oxidase-B inhibitor with neuroprotective activity. Prog Neurobiol 92(3):330–344. https://doi.org/10.1016/j.pneurobio.2010.06.008 CrossRefPubMed

Weinreb O, Amit T, Riederer P, Youdim MB, Mandel SA (2011) Neuroprotective profile of the multitarget drug rasagiline in Parkinson’s disease. Int Rev Neurobiol 100:127–149. https://doi.org/10.1016/b978-0-12-386467-3.00007-8 CrossRefPubMed

Weinreb O, Amit T, Bar-Am O, Youdim MB (2012) Ladostigil: a novel multimodal neuroprotective drug with cholinesterase and brain-selective monoamine oxidase inhibitory activities for Alzheimer’s disease treatment. Curr Drug Targets 13(4):483–494PubMedCrossRef

Whaley JG, Tharakan B, Smith B, Hunter FA, Childs EW (2009) (−)-Deprenyl inhibits thermal injury-induced apoptotic signaling and hyperpermeability in microvascular endothelial cells. J Burn Care Res 30(6):1018–1027. https://doi.org/10.1097/BCR.0b013e3181bfb825 CrossRefPubMed

Wilcock GK, Birks J, Whitehead A, Evans SJ (2002) The effect of selegiline in the treatment of people with Alzheimer’s disease: a meta-analysis of published trials. Int J Geriatr Psychiatry 17(2):175–183PubMedCrossRef

Yasar S, Schindler CW, Thorndike EB, Szelenyi I, Goldberg SR (1993) Evaluation of the stereoisomers of deprenyl for amphetamine-like discriminative stimulus effects in rats. J Pharmacol Exp Ther 265(1):1–6PubMed

Youdim M, Finberg JP, Levy R, Sterling J, Lerner D (1995) R-Enantiomers of N-propargyl-amino indian compounds. Their preparation and pharmaceuticals containing them. US Patent 5,457,133

Youdim MB, Gross A, Finberg JP (2001) Rasagiline [N-propargyl-1R(+)-aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br J Pharmacol 132(2):500–506. https://doi.org/10.1038/sj.bjp.0703826 CrossRefPubMedPubMedCentral

Zhao YJ, Wee HL, Au WL, Seah SH, Luo N, Li SC, Tan LC (2011) Selegiline use is associated with a slower progression in early Parkinson’s disease as evaluated by Hoehn and Yahr Stage transition times. Parkinsonism Relat Disord 17(3):194–197. https://doi.org/10.1016/j.parkreldis.2010.11.010 CrossRefPubMed

Title: Selegiline: a molecule with innovative potential
Authors: Tamás Tábi
László Vécsei
Moussa B. Youdim
Peter Riederer
Éva Szökő
Publication date: 01-05-2020
Publisher: Springer Vienna
Keywords: Parkinson's Disease
Levodopa
MAO-B Inhibitor
Rasagiline
Selegiline
Published in: Journal of Neural Transmission / Issue 5/2020
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-019-02082-0

At a glance: The STEP trials

Springer Medicine

Selegiline: a molecule with innovative potential

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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