Different Generations of Type-B Monoamine Oxidase Inhibitors in Parkinson’s Disease: From Bench to Bedside

Marika       Alborghetti; Ferdinando       Nicoletti
Abstract

Three inhibitors of type-B monoamine oxidase (MAOB), selegiline, rasagiline, and safinamide, are used for the treatment of Parkinson’s disease (PD). All three drugs improve motor signs of PD, and are effective in reducing motor fluctuations in patients undergoing long-term L-DOPA treatment. The effect of MAOB inhibitors on non-motor symptoms is not uniform and may not be class-related. Selegiline and rasagiline are irreversible inhibitors forming a covalent bond within the active site of MAOB. In contrast, safinamide is a reversible MAOB inhibitor, and also inhibits voltage- sensitive sodium channels and glutamate release. Safinamide is the prototype of a new generation of multi-active MAOB inhibitors, which includes the antiepileptic drug, zonisamide. Inhibition of MAOB-mediated dopamine metabolism largely accounts for the antiparkinsonian effect of the three drugs. Dopamine metabolism by MAOB generates reactive oxygen species, which contribute to nigro-striatal degeneration. Among all antiparkinsonian agents, MAOB inhibitors are those with the greatest neuroprotective potential because of inhibition of dopamine metabolism, induction of neurotrophic factors, and, in the case of safinamide, inhibition of glutamate release. The recent development of new experimental animal models that more closely mimic the progressive neurodegeneration associated with PD will allow to test the hypothesis that MAOB inhibitors may slow the progression of PD.
Keywords: Selegiline, rasagiline, safinamide, MAOB, basal ganglia, Parkinson's disease, glutamate release.
« Previous Next »
Graphical Abstract

[1] 
Titova, N.; Padmakumar, C.; Lewis, S.J.G.; Chaudhuri, K.R. Parkinson’s: a syndrome rather than a disease? J. Neural Transm. (Vienna),  2017, 124(8), 907-914.
[http://dx.doi.org/http://10.1007/s00702-016-1667-6] [PMID: 28028643] 
[2] 
Baltasar-Rodríguez, L.M.; Millán-Guerrero, R.O.; Aceves-Themsel, R.; Isais-Millán, S.; Delgado-Enciso, I. Longitudinal study of three families with familial Parkinson’s disease. Gac. Med. Mex.,  2006, 142(5), 387-391.
[PMID:  17128818] 
[3] 
Kalia, L.V.; Lang, A.E. Parkinson’s disease. Lancet,  2015, 386(9996), 896-912.
[http://dx.doi.org/http://10.1016/S0140-6736(14) 61393-3] [PMID: 25904081] 
[4] 
Schneider, S.A.; Alcalay, R.N. Neuropathology of genetic synucleinopathies with parkinsonism: Review of the literature. Mov. Disord.,  2017, 32(11), 1504-1523.
[http://dx.doi.org/http://10.1002/mds.27193] [PMID:  29124790] 
[5] 
Bose, A.; Beal, M.F. Mitochondrial dysfunction in Parkinson’s disease. J. Neurochem.,  2016, 139(Suppl. 1), 216-231.
[http://dx.doi.org/http://10.1111/jnc.13731] [PMID: 27546335] 
[6] 
Gao, G.; Wang, Z.; Lu, L.; Duan, C.; Wang, X.; Yang, H. Morphological analysis of mitochondria for evaluating the toxicity of α-synuclein in transgenic mice and isolated preparations by atomic force microscopy. Biomed. Pharmacother.,  2017, 96, 1380-1388.
[http://dx.doi.org/http://10.1016/j.biopha.2017.11.057] [PMID:  29169728] 
[7] 
Plotegher, N.; Berti, G.; Ferrari, E.; Tessari, I.; Zanetti, M.; Lunelli, L.; Greggio, E.; Bisaglia, M.; Veronesi, M.; Girotto, S.; Dalla Serra, M.; Perego, C.; Casella, L.; Bubacco, L. DOPAL derived alpha-synuclein oligomers impair synaptic vesicles physiological function. Sci. Rep.,  2017, 7, 40699.
[http://dx.doi.org/http://10.1038/srep40699] [PMID:  28084443] 
[8] 
Zhang, J.; Culp, M.L.; Craver, J.G.; Darley-Usmar, V. Mitochondrial function and autophagy: integrating proteotoxic, redox, and metabolic stress in Parkinson’s disease. J. Neurochem.,  2018, 144(6), 691-709.
[http://dx.doi.org/http://10.1111/jnc.14308] [PMID:  29341130] 
[9] 
Hinkle, J.T.; Perepezko, K.; Rosenthal, L.S.; Mills, K.A.; Pantelyat, A.; Mari, Z.; Tochen, L.; Bang, J.Y.; Gudavalli, M.; Yoritomo, N.; Butala, A.; Bakker, C.C.; Johnson, V.; Moukheiber, E.; Dawson, T.M.; Pontone, G.M. Markers of impaired motor and cognitive volition in Parkinson’s disease: Correlates of dopamine dysregulation syndrome, impulse control disorder, and dyskinesias. Parkinsonism Relat. Disord.,  2018, 47, 50-56.
[http://dx.doi.org/http://10.1016/j.parkreldis. 2017.11.338] [PMID:  29198499] 
[10] 
Picconi, B.; Hernández, L.F.; Obeso, J.A.; Calabresi, P. Motor complications in Parkinson’s disease: Striatal molecular and electrophysiological mechanisms of dyskinesias. Mov. Disord.,  2017, 33(6), 867-876.
[PMID:  29219207] 
[11] 
Morris, J.G. The management of Parkinson’s disease. Aust. N. Z. J. Med.,  1982, 12(2), 195-205.
[http://dx.doi.org/http://10.1111/j.1445-5994.1982.tb02460.x] [PMID:  7046720] 
[12] 
Blair, H.A.; Dhillon, S. Safinamide: A review in Parkinson’s disease. CNS Drugs,  2017, 31(2), 169-176.
[http://dx.doi.org/http://10.1007/s40263-017-0408-1] [PMID:  28110399] 
[13] 
Bonuccelli, U. Effects of safinamide on motor complications and pain in advancing Parkinson’s disease – Post Hoc analyses of pivotal trials. Eur. Neurol. Rev.,  2015, 10(2), 1-7.
[http://dx.doi.org/http://10.17925/ENR.2015.10.02.176] 
[14] 
Fabbrini, G.; Abbruzzese, G.; Marconi, S.; Zappia, M. Selegiline: a reappraisal of its role in Parkinson disease. Clin. Neuropharmacol.,  2012, 35(3), 134-140.
[http://dx.doi.org/http://10.1097/WNF.0b013e 318255838b] [PMID:  22592509] 
[15] 
McCormack, P.L. Rasagiline: A review of its use in the treatment of idiopathic Parkinson’s disease. CNS Drugs,  2014, 28(11), 1083-1097.
[http://dx.doi.org/http://10.1007/s40263-014-0206-y] [PMID:  25322951] 
[16] 
Miklya, I. The significance of selegiline/(-)-deprenyl after 50 years in research and therapy (1965-2015). Mol. Psychiatry,  2016, 21(11), 1499-1503.
[http://dx.doi.org/http://10.1038/mp.2016.127] [PMID:  27480491] 
[17] 
Stocchi, F.; Fossati, C.; Torti, M. Rasagiline for the treatment of Parkinson’s disease: an update. Expert Opin. Pharmacother.,  2015, 16(14), 2231-2241.
[http://dx.doi.org/http://10.1517/14656566.2015. 1086748] [PMID:  26364897] 
[18] 
Jenner, P.; Marsden, C.D. The actions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in animals as a model of Parkinson’s disease. J. Neural Transm. Suppl.,  1986, 20, 11-39.
[PMID:  3091760] 
[19] 
Binda, C.; Li, M.; Hubalek, F.; Restelli, N.; Edmondson, D.E.; Mattevi, A. Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures. Proc. Natl. Acad. Sci. U.S.A,  2003, 100(17), 9750-9755.
[http://dx.doi.org/http://10.1073/pnas.1633804100] 
[20] 
Binda, C.; Hubálek, F.; Li, M.; Herzig, Y.; Sterling, J.; Edmondson, D.E.; Mattevi, A. Binding of rasagiline-related inhibitors to human monoamine oxidases: a kinetic and crystallographic analysis. J. Med. Chem.,  2005, 48(26), 8148-8154.
[21] 
Nagy, J.; Kalàsz, H. Selegiline binding to monoamine oxidase enzyme in the rear view mirror. RJLBPCS,  2017, 3(2), 99-108.
[22] 
Fowler, J.S.; Volkow, N.D.; Logan, J.; Wang, G.J.; MacGregor, R.R.; Schyler, D.; Wolf, A.P.; Pappas, N.; Alexoff, D.; Shea, C. Slow recovery of human brain MAO B after L-deprenyl (Selegeline) withdrawal. Synapse,  1994, 18(2), 86-93.
[http://dx.doi.org/http://10.1002/syn.890180203] [PMID:  7839316] 
[23] 
Freedman, N.M.; Mishani, E.; Krausz, Y.; Weininger, J.; Lester, H.; Blaugrund, E.; Ehrlich, D.; Chisin, R. In vivo measurement of brain monoamine oxidase B occupancy by rasagiline, using (11)C-l-deprenyl and PET. J. Nucl. Med.,  2005, 46(10), 1618-1624.
[PMID:  16204711] 
[24] 
Caccia, C.; Maj, R.; Calabresi, M.; Maestroni, S.; Faravelli, L.; Curatolo, L.; Salvati, P.; Fariello, R.G. Safinamide: from molecular targets to a new anti-Parkinson drug. Neurology,  2006, 67(7) (Suppl. 2), S18-S23.
[http://dx.doi.org/10.1212/WNL.67.7_suppl_2.S18] [PMID: 17030736] 
[25] 
Leonetti, F.; Capaldi, C.; Pisani, L.; Nicolotti, O.; Muncipinto, G.; Stefanachi, A.; Cellamare, S.; Caccia, C.; Carotti, A. Solid-phase synthesis and insights into structure-activity relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase. J. Med. Chem.,  2007, 50(20), 4909-4916.
[http://dx.doi.org/http://10.1021/jm070725e] [PMID:  17824599] 
[26] 
Youdim, M.B.; Gross, A.; Finberg, J.P. Rasagiline N-propargyl-1R(+)-aminoindan, a selective and potent inhibitor of mitochondrial monoamine oxidase B. Br. J. Pharmacol.,  2001, 132(2), 500-506.
[http://dx.doi.org/http://10.1038/sj.bjp.0703826] [PMID:  11159700] 
[27] 
Lecht, S.; Haroutiunian, S.; Hoffman, A.; Lazarovici, P. Rasagiline - a novel MAO B inhibitor in Parkinson’s disease therapy. Ther. Clin. Risk Manag.,  2007, 3(3), 467-474.
[PMID:  18488080] 
[28] 
Marzo, A.; Dal Bo, L.; Monti, N.C.; Crivelli, F.; Ismaili, S.; Caccia, C.; Cattaneo, C.; Fariello, R.G. Pharmacokinetics and pharmacodynamics of safinamide, a neuroprotectant with antiparkinsonian and anticonvulsant activity. Pharmacol. Res.,  2004, 50(1), 77-85.
[http://dx.doi.org/http://10.1016/j.phrs.2003.12.004] [PMID:  15082032] 
[29] 
Stocchi, F.; Torti, M. Adjuvant therapies for Parkinson’s disease: critical evaluation of safinamide. Drug Des. Devel. Ther.,  2016, 10, 609-618.
[http://dx.doi.org/http://10.2147/DDDT.S77749] [PMID:  26917951] 
[30] 
Bartl, J.; Müller, T.; Grünblatt, E.; Gerlach, M.; Riederer, P. Chronic monoamine oxidase-B inhibitor treatment blocks monoamine oxidase-A enzyme activity. J. Neural Transm. (Vienna),  2014, 121(4), 379-383.
[http://dx.doi.org/http://10.1007/s00702-013-1120-z] [PMID:  24272680] 
[31] 
Müller, T.; Riederer, P.; Grünblatt, E. Determination of monoamine oxidase A and B activity in long-term treated patients with parkinson disease. Clin. Neuropharmacol.,  2017, 40(5), 208-211.
[http://dx.doi.org/http://10.1097/WNF.0000000000000233] [PMID:  28682929] 
[32] 
Salvati, P.; Maj, R.; Caccia, C.; Cervini, M.A.; Fornaretto, M.G.; Lamberti, E.; Pevarello, P.; Skeen, G.A.; White, H.S.; Wolf, H.H.; Faravelli, L.; Mazzanti, M.; Mancinelli, E.; Varasi, M.; Fariello, R.G. Biochemical and electrophysiological studies on the mechanism of action of PNU-151774E, a novel antiepileptic compound. J. Pharmacol. Exp. Ther.,  1999, 288(3), 1151-1159.
[PMID:  10027853] 
[33] 
Morari, M.; Brugnoli, A.; Pisanò, C.A.; Novello, S.; Caccia, C.; Melloni, E.; Padoani, G.; Vailati, S.; Sardina, M. Safinamide differentially modulates In Vivo glutamate and GABA release in the rat hippocampus and basal ganglia. J. Pharmacol. Exp. Ther.,  2018, 364(2), 198-206.
[http://dx.doi.org/http://10.1124/jpet.117.245100] [PMID:  29167350] 
[34] 
Sonsalla, P.K.; Wong, L.Y.; Winnik, B.; Buckley, B. The antiepileptic drug zonisamide inhibits MAO-B and attenuates MPTP toxicity in mice: clinical relevance. Exp. Neurol.,  2010, 221(2), 329-334.
[http://dx.doi.org/http://10.1016/j.expneurol.2009.11.018] [PMID:  19948168] 
[35] 
Fox, S.H.; Katzenschlager, R.; Lim, S.Y.; Barton, B.; de Bie, R.M.A.; Seppi, K.; Coelho, M.; Sampaio, C. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson’s disease. Mov. Disord.,  2018, 33(8), 1248-1266.
[http://dx.doi.org/http://10.1002/mds.27372] [PMID:  29570866] 
[36] 
Uemura, M.T.; Asano, T.; Hikawa, R.; Yamakado, H.; Takahashi, R. Zonisamide inhibits monoamine oxidase and enhances motor performance and social activity. Neurosci. Res.,  2017, 124, 25-32.
[http://dx.doi.org/http://10.1016/j.neures.2017.05.008] [PMID:  28624436] 
[37] 
Heinonen, E.H.; Anttila, M.I.; Karnani, H.L.; Nyman, L.M.; Vuorinen, J.A.; Pyykkö, K.A.; Lammintausta, R.A. Desmethylselegiline, a metabolite of selegiline, is an irreversible inhibitor of monoamine oxidase type B in humans. J. Clin. Pharmacol.,  1997, 37(7), 602-609.
[http://dx.doi.org/http://10.1002/j.1552-4604.1997.tb04342. x] [PMID:  9243353] 
[38] 
Mahmood, I. Clinical pharmacokinetics and pharmacodynamics of selegiline. An update. Clin. Pharmacokinet.,  1997, 33(2), 91-102.
[http://dx.doi.org/http://10.2165/00003088-199733020-00002] [PMID:  9260033] 
[39] 
Benetton, S.A.; Fang, C.; Yang, Y.O.; Alok, R.; Year, M.; Lin, C.C.; Yeh, L.T. P450 phenotyping of the metabolism of selegiline to desmethylselegiline and methamphetamine. Drug Metab. Pharmacokinet.,  2007, 22(2), 78-87.
[http://dx.doi.org/http://10.2133/dmpk.22.78] 
[40] 
Nishiya, Y.; Hagihara, K.; Ito, T.; Tajima, M.; Miura, S.; Kurihara, A.; Farid, N.A.; Ikeda, T. Mechanism-based inhibition of human cytochrome P450 2B6 by ticlopidine, clopidogrel, and the thiolactone metabolite of prasugrel. Drug Metab. Dispos.,  2009, 37(3), 589-593.
[http://dx.doi.org/http://10.1124/dmd.108.022988] [PMID:  19047469] 
[41] 
Chen, J.J.; Ly, A.V. Rasagiline: A second-generation monoamine oxidase type-B inhibitor for the treatment of Parkinson’s disease. Am. J. Health Syst. Pharm.,  2006, 63(10), 915-928.
[http://dx.doi.org/http://10.2146/ajhp050395] [PMID:  16675649] 
[42] 
New drug treatment for Parkinson’s disease. FDA Consum.,  2006, 40(4), 7.
[PMID:  17245831] 
[43] 
Elmer, L.; Davis, K.; Fazzini, E.; Chin, L.; Scott, B.; Wilcox, C.; Colcher, A.; Reichwein, S.; Hauser, R.; Gauge, L.; Leehey, M.; Ondo, W.; Lewitt, P.; Kaminski, P.; Harrison, M.; Rost-Ruffner, E.; Racette, B.; Cooper, P.; Frei, K.; Luong, N.; Pahwa, R.; Dicarlo, J.; Lew, M.F.; Kawai, C.; Jennings, D.; Caplan, K.; Fink, J.S.; Novak, P.; Thomas, C.; Chouinard, S.; Beauvais, C.; Tabbal, S.; Uc, E.; Patterson, J.; Fernandez, H.; Bertoni, J.M.; Skrypnik, L.; Panisset, M.; Fortin, M.J.; Molho, E.; Nash, J.; Dalvi, A.; Schwieterman, D.; Goetz, C.; Janko, K.; Mendis, T.; Mahtat, D.; Gray, P.; Camicioli, R.; King, P.; Wojcieszek, J.; Kumar, R.; Judd, D.; Margolin, D.; Margolin, J.J.; Clem, F.; Gordon, P.; Marshall, F.; Berry, D.; Rottenberg, D.; Hansen, J.; Gordon, M.F.; Hassan, M.; Keltonic, P.; Hermanowicz, N.; Niswonger, S.; Jog, M.; Horn, C.; Shulman, L.; Cines, M.; Suchowersky, O.; Furtado, S.; Derwent, L.; Samanta, J.; Williamson, K.; Ramos, C.S.; Berrios, L.; Roque, S.; Sutton, J.; Young, J.; Waters, C.; Benabou, R.; Singer, C.; Koller, W.; Martin, D.; Sethi, K.; Carpenter, J.; Rao, J.; Cook, M.; Feigin, A.; Cox, M.; Riley, D.; Calabrese, V.; Standaert, D.; Tennis, M.; Manyam, B.; Whetteckey, J.; Wulbrecht, B.; Rajput, A.; Golbe, L.; Caputo, D.; Freeman, A.; McGinn, L.; Subramanian, T.; Ajax, T.; Aminoff, M.; Hevezi, J.; So, J. A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: The PRESTO study. Arch. Neurol.,  2005, 62(2), 241-248.
[http://dx.doi.org/http://10.1001/archneur.62.2.241] [PMID:  15710852] 
[44] 
Brouwers, E.E.; Söhne, M.; Kuipers, S.; van Gorp, E.C.; Schellens, J.H.; Koks, C.H.; Beijnen, J.H.; Huitema, A.D. Ciprofloxacin strongly inhibits clozapine metabolism: two case reports. Clin. Drug Investig.,  2009, 29(1), 59-63.
[http://dx.doi.org/http://10.2165/0044011-200929010-00006] [PMID:  19067475] 
[45] 
Spina, E.; Santoro, V.; D’Arrigo, C. Clinically relevant pharmacokinetic drug interactions with second-generation antidepressants: an update. Clin. Ther.,  2008, 30(7), 1206-1227.
[http://dx.doi.org/http:// 10.1016/S0149-2918(08)80047-1] [PMID:  18691982] 
[46] 
Zvyaga, T.; Chang, S.Y.; Chen, C.; Yang, Z.; Vuppugalla, R.; Hurley, J.; Thorndike, D.; Wagner, A.; Chimalakonda, A.; Rodrigues, A.D. Evaluation of six proton pump inhibitors as inhibitors of various human cytochromes P450: focus on cytochrome P450 2C19. Drug Metab. Dispos.,  2012, 40(9), 1698-1711.
[http://dx.doi.org/http://10.1124/dmd.112.045575] [PMID:  22648560] 
[47] 
Yapici Eser, H.; Bora, H.A.; Kuruoğlu, A. Depression and Parkinson disease: Prevalence, temporal relationship, and determinants. Turk. J. Med. Sci.,  2017, 47(2), 499-503.
[http://dx.doi.org/http://10. 3906/sag-1603-101] [PMID:  28425238] 
[48] 
Onofrj, M.; Bonanni, L.; Thomas, A. An expert opinion on safinamide in Parkinson’s disease. Expert Opin. Investig. Drugs,  2008, 17(7), 1115-1125.
[http://dx.doi.org/http://10.1517/13543784.17.7.1115] [PMID:  18549347] 
[49] 
Conn, P.J.; Battaglia, G.; Marino, M.J.; Nicoletti, F. Metabotropic glutamate receptors in the basal ganglia motor circuit. Nat. Rev. Neurosci.,  2005, 6(10), 787-798.
[http://dx.doi.org/http://10.1038/nrn1763] [PMID:  16276355] 
[50] 
Cenci, M.A.; Ohlin, K.E.; Odin, P. Current options and future possibilities for the treatment of dyskinesia and motor fluctuations in Parkinson’s disease. CNS Neurol. Disord. Drug Targets,  2011, 10(6), 670-684.
[http://dx.doi.org/http://10.2174/187152711797247885] [PMID:  21838677] 
[51] 
Sebastianutto, I.; Cenci, M.A. mGlu receptors in the treatment of Parkinson’s disease and L-DOPA-induced dyskinesia. Curr. Opin. Pharmacol.,  2018, 38, 81-89.
[http://dx.doi.org/http://10.1016/j.coph. 2018.03.003] [PMID:  29625424] 
[52] 
Magyar, K. The pharmacology of selegiline. Int. Rev. Neurobiol.,  2011, 100, 65-84.
[http://dx.doi.org/http://10.1016/B978-0-12-386467-3.00004-2] [PMID:  21971003] 
[53] 
Koller, K.; Olanow, W.; Rodnitzky, R.; Fink, J.S.; Growdon, J.H.; Paulson, G.; Kurlan, R.; Friedman, J.H.; Gancher, S.; Nutt, J.; Rajput, A.H.; Bennett, J.; Wooten, J.F.; LeWitt, P.; Goetz, C.; Tanner, C.; Shannon, K.; Klawans, H.; Suchowersky, O.; Brin, M.; Bressman, S.; Weiner, W.; Sanchez-Ramos, J.; Jankovic, J.; Penney, J.B.; Lang, A.; Hoehn, M.; Tetrud, J.; Grimes, J.D.; Pfeiffer, R.; Shults, C.; Thal, L.; Gauthier, S.; Golbe, L.I.; Perlmutter, J.S.; Moses, III H.; Hurtig, H.I.; Stern, M. Effect of deprenyl on the progression of disability in early Parkinson’s disease. N. Engl. J. Med.,  1989, 321(20), 1364-1371.
[http://dx.doi.org/http://10.1056/NEJM198911163212004] [PMID:  2509910] 
[54] 
Olanow, C.W.; Hauser, R.A.; Gauger, L.; Malapira, T.; Koller, W.; Hubble, J.; Bushenbark, K.; Lilienfeld, D.; Esterlitz, J. The effect of deprenyl and levodopa on the progression of Parkinson’s disease. Ann. Neurol.,  1995, 38(5), 771-777.
[http://dx.doi.org/http://10. 1002/ana.410380512] [PMID:  7486869] 
[55] 
Myllylä, V.V.; Sotaniemi, K.; Mäki-Ikola, O.; Rinne, U.K.; Heinonen, E.H. Role of selegiline in combination therapy of Parkinson’s disease. Neurology,  1996, 47(6)(Suppl. 3), S200-S209.
[http://dx.doi.org/http:// 10.1212/WNL.47.6_Suppl_3.200S] [PMID:  8959989] 
[56] 
Shoulson, F.; Kieburtz, S.; Oakes, S.; Blindauer, O.; Goren, L.; Plumb, E.; Lew, H.; Lloyd, H.; Golbe, W.; Feigin, O.; Calabrese, A.; Marshall, M.T.; Mendis, N.; Mendis, H.; Pahwa, M.; Shulman, R.; Stacy, B.; Tuite, K.; Shannon, T.; Marek, A.; Dowling, K.; Sethi, M. Adler, LeWitt.; Gordon, F. S.; and Salzman, M.D.; Shinaman, B.; Gauger, B.; Klimek, B.; Shannon, H.; Berry, G.; Del Rizzo, G.; Betcher, B.; Ewanishin, W.; Peterson, E.; Jaglin, K.; Stavris, DiMinno.; Richman, K.; McInnes, DeAngelis.; Winnick, T.; Evans, L.; Roberge, C.; Connolly, D.O.; and Josephson, and Mr. Chadwick, S., Shoulson, O., Fahn, K.; Blindauer, S.; Schwid, Lang.; White, N.; Cox, E.; Bausch, I.; Plumb, S.; Shoulson, O.; Kieburtz, F.; Blindauer, S.; Schwid, S.; Fahn, K.; Stern, O.; Siderowf, B.; Lew, H.; Loyd, H.; Golbe, W.; Feigin, O.; Calabrese, A.; Marshall, Miyasaki, T. M.N.; Mendis, H.; Pahwa, M.; Shulman, R.; Stacy, B.; Tuite, K. S.; Tanner, M.; Aminoff, D.; Kang, S.; Martin, A.; LeWitt, G.; Feldman, L.; White, S.; Cox, N.; Goren, O. S.; Levy, Mss, D.; Shinaman, B.; Gauger, B.; Klimek, B.; Shannon, H.; Berry, G.; Del Rizzo, G.; Betcher, B.; Ewanishin, W.; Peterson, E.; Jaglin, K.; Stavris, DiMinno, Richman, K.; McInnes, DeAngelis, Winnick, T.; Plumb, E.; Lind, R.; Conn, C.; Daigneault, O.; Josephson, I. E. B.; Mr Chadwick, O.; Cox, M. E.; Bausch, I.; Eyal, S. K.; Day, S.; Lew, H.; Loyd, H.; Golbe, W.; Feigin, O.; Calabrese, A.; Marshall, M.T.; Mendis, N.; Mendis, H.; Pahwa, M.; Shulman, R.; Stacy, B.; Tuite, K. S.; Tanner, M.; Aminoff, D.; Kang, S.; Martin, A.; LeWitt, G.; Feldman, L.; White, N.; Salzman, G. O.; Levy, B.; Gauger, B.; Klimek, B. Shannon, H.; Berry, G.; Del Rizzo, G.; Betcher, B.; Ewanishin, W.; Peterson, E.; Jaglin, K.; Stavris, DiMinno.; Richman, K.; McInnes, DeAngelis.; Winnick, T.; Evans, L.; Roberge, C.; Connolly, D.; Oliva, J.; Chadwick, S.; Siderowf, F.; Kieburtz, B.; Schwid, S.P. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch. Neurol.,  2004, 61(4), 561-566.
[http://dx.doi.org/http://10.1001/archneur.61.4.561] [PMID:  15096406] 
[57] 
Olanow, C.W.; Rascol, O.; Hauser, R.; Feigin, P.D.; Jankovic, J.; Lang, A.; Langston, W.; Melamed, E.; Poewe, W.; Stocchi, F.; Tolosa, E. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N. Engl. J. Med.,  2009, 361(13), 1268-1278.
[http://dx.doi.org/http:// 10.1056/NEJMoa0809335] [PMID:  19776408] 
[58] 
Jankovic, J.; Berkovich, E.; Eyal, E.; Tolosa, E. Symptomatic efficacy of rasagiline monotherapy in early Parkinson’s disease: post-hoc analyses from the ADAGIO trial. Parkinsonism Relat. Disord.,  2014, 20(6), 640-643.
[http://dx.doi.org/http://10.1016/j.parkreldis.2014. 02.024] [PMID:  24637126] 
[59] 
Rascol, O.; Brooks, D.J.; Melamed, E.; Oertel, W.; Poewe, W.; Stocchi, F.; Tolosa, E. 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,  2005, 365(9463), 947-954.
[http://dx.doi.org/http://10.1016/S0140-6736(05)71083-7] [PMID:  15766996] 
[60] 
Elmer, L.W. Rasagiline adjunct therapy in patients with Parkinson’s disease: post hoc analyses of the PRESTO and LARGO trials. Parkinsonism Relat. Disord.,  2013, 19(11), 930-936.
[http://dx.doi.org/http://10.1016/j.parkreldis.2013.06.001] [PMID:  23849501] 
[61] 
Cereda, E.; Cilia, R.; Canesi, M.; Tesei, S.; Mariani, C.B.; Zecchinelli, A.L.; Pezzoli, G. Efficacy of rasagiline and selegiline in Parkinson’s disease: a head-to-head 3-year retrospective case-control study. J. Neurol.,  2017, 264(6), 1254-1263.
[http://dx.doi.org/http://10. 1007/s00415-017-8523-y] [PMID:  28550482] 
[62] 
Dashtipour, K.; Chen, J.J.; Kani, C.; Bahjri, K.; Ghamsary, M. Clinical outcomes in patients with Parkinson’s disease treated with a monoamine oxidase Type-B inhibitor: A cross-sectional, cohort study. Pharmacotherapy,  2015, 35(7), 681-686.
[http://dx.doi.org/http://10.1002/phar.1611] [PMID:  26139574] 
[63] 
Fasano, A.; Di Matteo, A.; Vitale, C.; Squintani, G.; Ferigo, L.; Bombieri, F.; Santangelo, G.; Amboni, M.; Barone, P.; Tinazzi, M. Reversible Pisa syndrome in patients with Parkinson’s disease on rasagiline therapy. Mov. Disord.,  2011, 26(14), 2578-2580.
[http://dx.doi.org/http://10.1002/mds.23918] [PMID:  22170277] 
[64] 
Valentino, F.; Cosentino, G.; Fierro, B.; Realmuto, S.; Mastrilli, S.; Savettieri, G.; D’Amelio, M. Pisa syndrome after rasagiline therapy in a patient with Parkinson’s disease. Neurol. Sci.,  2015, 36(12), 2305.
[http://dx.doi.org/http://10.1007/s10072-015-2374-z] [PMID:  26335016] 
[65] 
Gubellini, P.; Pisani, A.; Centonze, D.; Bernardi, G.; Calabresi, P. Metabotropic glutamate receptors and striatal synaptic plasticity: implications for neurological diseases. Prog. Neurobiol.,  2004, 74(5), 271-300.
[http://dx.doi.org/http://10.1016/j.pneurobio.2004.09.005] [PMID:  15582223] 
[66] 
Picconi, B.; Centonze, D.; Håkansson, K.; Bernardi, G.; Greengard, P.; Fisone, G.; Cenci, M.A.; Calabresi, P. Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat. Neurosci.,  2003, 6(5), 501-506.
[http://dx.doi.org/http://10.1038/nn1040] [PMID:  12665799] 
[67] 
Picconi, B.; Paillé, V.; Ghiglieri, V.; Bagetta, V.; Barone, I.; Lindgren, H.S.; Bernardi, G.; Angela, C.M.; Calabresi, P. l-DOPA dosage is critically involved in dyskinesia via loss of synaptic depotentiation. Neurobiol. Dis.,  2008, 29(2), 327-335.
[http://dx.doi.org/http://10.1016/j.nbd.2007.10.001] [PMID:  17997101] 
[68] 
Sgambato-Faure, V.; Cenci, M.A. Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson’s disease. Prog. Neurobiol.,  2012, 96(1), 69-86.
[http://dx.doi.org/http://10.1016/j. pneurobio.2011.10.005] [PMID:  22075179] 
[69] 
Grégoire, L.; Jourdain, V.A.; Townsend, M.; Roach, A.; Di Paolo, T. Safinamide reduces dyskinesias and prolongs L-DOPA antiparkinsonian effect in parkinsonian monkeys. Parkinsonism Relat. Disord.,  2013, 19(5), 508-514.
[http://dx.doi.org/http://10.1016/j.parkreldis. 2013.01.009] [PMID:  23402994] 
[70] 
Borgohain, R.; Szasz, J.; Stanzione, P.; Meshram, C.; Bhatt, M.; Chirilineau, D.; Stocchi, F.; Lucini, V.; Giuliani, R.; Forrest, E.; Rice, P.; Anand, R. Randomized trial of safinamide add-on to levodopa in Parkinson’s disease with motor fluctuations. Mov. Disord.,  2014, 29(2), 229-237.
[http://dx.doi.org/http://10.1002/mds.25751] [PMID:  24323641] 
[71] 
Borgohain, R.; Szasz, J.; Stanzione, P.; Meshram, C.; Bhatt, M.H.; Chirilineau, D.; Stocchi, F.; Lucini, V.; Giuliani, R.; Forrest, E.; Rice, P.; Anand, R. Two-year, randomized, controlled study of safinamide as add-on to levodopa in mid to late Parkinson’s disease. Mov. Disord.,  2014, 29(10), 1273-1280.
[http://dx.doi.org/http://10. 1002/mds.25961] [PMID:  25044402] 
[72] 
Cattaneo, C.; Ferla, R.L.; Bonizzoni, E.; Sardina, M. Long-Term Effects of safinamide on dyskinesia in mid- to late-stage Parkinson’s disease: A post-Hoc analysis. J. Parkinsons Dis.,  2015, 5(3), 475-481.
[http://dx.doi.org/http://10.3233/JPD-150569] [PMID:  26406127] 
[73] 
Murata, M.; Hasegawa, K.; Kanazawa, I.; Fukasaka, J.; Kochi, K.; Shimazu, R. Zonisamide improves wearing-off in Parkinson’s disease: A randomized, double-blind study. Mov. Disord.,  2015, 30(10), 1343-1350.
[http://dx.doi.org/http://10.1002/mds.26286] [PMID:  26094993] 
[74] 
Barone, P.; Santangelo, G.; Morgante, L.; Onofrj, M.; Meco, G.; Abbruzzese, G.; Bonuccelli, U.; Cossu, G.; Pezzoli, G.; Stanzione, P.; Lopiano, L.; Antonini, A.; Tinazzi, M. A randomized clinical trial to evaluate the effects of rasagiline on depressive symptoms in non-demented Parkinson’s disease patients. Eur. J. Neurol.,  2015, 22(8), 1184-1191.
[http://dx.doi.org/http://10.1111/ene.12724] [PMID:  25962410] 
[75] 
Kasai, S.; Yoshihara, T.; Lopatina, O.; Ishihara, K.; Higashida, H. Selegiline ameliorates depression-like behavior in mice lacking the CD157/BST1 gene, a risk factor for Parkinson’s disease. Front. Behav. Neurosci.,  2017, 11, 75.
[http://dx.doi.org/http://10.3389/fnbeh.2017.00075] [PMID:  28515684] 
[76] 
Contreras-Mora, H.; Rowland, M.A.; Yohn, S.E.; Correa, M.; Salamone, J.D. Partial reversal of the effort-related motivational effects of tetrabenazine with the MAO-B inhibitor deprenyl (selegiline): Implications for treating motivational dysfunctions. Pharmacol. Biochem. Behav.,  2018, 166, 13-20.
[http://dx.doi.org/http:// 10.1016/j.pbb.2018.01.001] [PMID:  29309800] 
[77] 
Amiri, S.; Amini-Khoei, H.; Mohammadi-Asl, A.; Alijanpour, S.; Haj-Mirzaian, A.; Rahimi-Balaei, M.; Razmi, A.; Olson, C.O.; Rastegar, M.; Mehdizadeh, M.; Zarrindast, M.R. Involvement of D1 and D2 dopamine receptors in the antidepressant-like effects of selegiline in maternal separation model of mouse. Physiol. Behav.,  2016, 163, 107-114.
[http://dx.doi.org/http://10.1016/j.physbeh.2016.04. 052] [PMID:  27143252] 
[78] 
Cristancho, M.A.; Thase, M.E. Critical appraisal of selegiline transdermal system for major depressive disorder. Expert Opin. Drug Deliv.,  2016, 13(5), 659-665.
[http://dx.doi.org/http://10.1517/17425247.2016.1140145] [PMID:  26837935] 
[79] 
Stocchi, F. Benefits of treatment with rasagiline for fatigue symptoms in patients with early Parkinson’s disease. Eur. J. Neurol.,  2014, 21(2), 357-360.
[http://dx.doi.org/http://10.1111/ene.12205] [PMID:  23790011] 
[80] 
Poewe, W.; Hauser, R.A.; Lang, A. Effects of rasagiline on the progression of nonmotor scores of the MDS-UPDRS. Mov. Disord.,  2015, 30(4), 589-592.
[http://dx.doi.org/http://10.1002/mds.26124] [PMID:  25545629] 
[81] 
Cattaneo, C.; Müller, T.; Bonizzoni, E.; Lazzeri, G.; Kottakis, I.; Keywood, C. Long-term effects of safinamide on mood fluctuations in Parkinson’s Disease. J. Parkinsons Dis.,  2017, 7(4), 629-634.
[http://dx.doi.org/http://10.3233/JPD-171143] [PMID:  28777756] 
[82] 
Cattaneo, C.; Kulisevsky, J.; Tubazio, V.; Castellani, P. Long-term Efficacy of Safinamide on Parkinson’s Disease chronic pain. Adv. Ther.,  2018, 35(4), 515-522.
[http://dx.doi.org/http://10.1007/s12325-018-0687-z] [PMID:  29542008] 
[83] 
Cattaneo, C.; Barone, P.; Bonizzoni, E.; Sardina, M. Effects of safinamide on pain in fluctuating Parkinson’s disease patients: A post-Hoc analysis. J. Parkinsons Dis.,  2017, 7(1), 95-101.
[http://dx.doi.org/http://10.3233/JPD-160911] [PMID:  27802242] 
[84] 
Liguori, C.; Mercuri, N.B.; Stefani, A.; Pierantozzi, M. Effective treatment of restless legs syndrome by safinamide in Parkinson’s disease patients. Sleep Med.,  2018, 41, 113-114.
[http://dx.doi.org/http://dx.doi. org/10.1016/j.sleep.2017.09.017] [PMID:  29268951] 
[85] 
Vermersch, P.; Petit, H. Long-term selegiline tolerance in the treatment of Parkinson’s disease. Therapie,  1992, 47(1), 75-78.
[PMID:  1523599] 
[86] 
Parkinson Study Group. Mortality in DATATOP. A multicenter trial in early Parkinson’s disease. Ann. Neurol.,  1998, 43(3), 318-325.
[http://dx.doi.org/http://10. 1002/ana.410430309] [PMID:  9506548] 
[87] 
Montastruc, J.L.; Chaumerliac, C.; Desboeuf, K.; Manika, M.; Bagheri, H.; Rascol, O.; Lapeyre-Mestre, M. Adverse drug reactions to selegiline: a review of the French pharmacovigilance database. Clin. Neuropharmacol.,  2000, 23(5), 271-275.
[http://dx.doi.org/http://dx.doi. org/10.1097/00002826-200009000-00006] [PMID:  11154095] 
[88] 
Chen, J.J.; Swope, D.M.; Dashtipour, K. Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson’s disease. Clin. Ther.,  2007, 29(9), 1825-1849.
[http://dx.doi.org/http://10.1016/j.clinthera.2007.09.021] [PMID:  18035186] 
[89] 
deMarcaida, J.A.; Schwid, S.R.; White, W.B.; Blindauer, K.; Fahn, S.; Kieburtz, K.; Stern, M.; Shoulson, I. Effects of tyramine administration in Parkinson’s disease patients treated with selective MAO-B inhibitor rasagiline. Mov. Disord.,  2006, 21(10), 1716-1721.
[http://dx.doi.org/http://10.1002/mds.21048] [PMID:  16856145] 
[90] 
Müller, T.; Hoffmann, J.A.; Dimpfel, W.; Oehlwein, C. Switch from selegiline to rasagiline is beneficial in patients with Parkinson’s disease. J. Neural Transm. (Vienna),  2013, 120(5), 761-765.
[http://dx.doi.org/http://10.1007/s00702-012-0927-3] [PMID:  23196982] 
[91] 
Sharma, T.; Anand, R.; Stocchi, F.; Borgohain, R.; Rossetti, R. 015 Study Group. Cognitive effects of Safinamide in early Parkinson’s disease patients. International Congress of Parkinson’s Disease and Movement Disorders 2007 June 3-7Istanbul, Turkey, 
[92] 
Stocchi, F.; Borgohain, R.; Onofrj, M.; Schapira, A.H.; Bhatt, M.; Lucini, V.; Giuliani, R.; Anand, R. A randomized, double-blind, placebo-controlled trial of safinamide as add-on therapy in early Parkinson’s disease patients. Mov. Disord.,  2012, 27(1), 106-112.
[http://dx.doi.org/http://10.1002/mds.23954] [PMID:  21913224] 
[93] 
Schapira, A.H.; Stocchi, F.; Borgohain, R.; Onofrj, M.; Bhatt, M.; Lorenzana, P.; Lucini, V.; Giuliani, R.; Anand, R. Long-term efficacy and safety of safinamide as add-on therapy in early Parkinson’s disease. Eur. J. Neurol.,  2013, 20(2), 271-280.
[http://dx.doi.org/http://10.1111/j.1468-1331.2012.03840.x] [PMID:  22967035] 
[94] 
Aboukarr, A.; Giudice, M. Interaction between monoamine oxidase B inhibitors and selective serotonin reuptake inhibitors. Can. J. Hosp. Pharm.,  2018, 71(3), 196-207.
[http://dx.doi.org/http://10.4212/cjhp.v71i3.2586] [PMID:  29955193] 
[95] 
Chen, J.J.; Berchou, R.C. Low incidence of cognitive and behavioral adverse events in rasagiline-treated patients with early to advanced Parkinson’s disease. Pkarmacotkerapy.,  2005, 25, 1466.
[96] 
Elmer, L.; Schwid, S.; Eberly, S.; Goetz, C.; Fahn, S.; Kieburtz, K.; Oakes, D.; Blindauer, K.; Salzman, P.; Oren, S.; Prisco, U.L.; Stern, M.; Shoulson, I. Rasagiline-associated motor improvement in PD occurs without worsening of cognitive and behavioral symptoms. J. Neurol. Sci.,  2006, 248(1-2), 78-83.
[http://dx.doi.org/http:// 10.1016/j.jns.2006.05.014] [PMID:  16828804] 
[97] 
Goetz, C.G.; Schwid, S.R.; Eberly, S.W.; Oakes, D.; Shoulson, I. Safety of rasagiline in elderly patients with Parkinson disease. Neurology,  2006, 66(9), 1427-1429.
[http://dx.doi.org/http://10.1212/01.wnl. 0000210692.95595.1c] [PMID:  16682679] 
[98] 
Riederer, P.; Müller, T. Use of monoamine oxidase inhibitors in chronic neurodegeneration. Expert Opin. Drug Metab. Toxicol.,  2017, 13(2), 233-240.
[http://dx.doi.org/http://10.1080/17425255.2017. 1273901] [PMID:  27998194] 
[99] 
Parkinson’s Study Group. Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. N. Engl. J. Med.,  1993, 328(3), 176-183.
[http://dx.doi.org/http://10.1056/NEJM199301213280305] [PMID:  8417384] 
[100] 
Fowler, J.S.; Volkow, N.D.; Logan, J.; Wang, G.J.; MacGregor, R.R.; Schyler, D.; Wolf, A.P.; Pappas, N.; Alexoff, D.; Shea, C. Slow recovery of human brain MAO B after L-deprenyl (Selegeline) withdrawal. Synapse,  1994, 18(2), 86-93.
[http://dx.doi.org/http://dx.doi. org/10.1002/syn.890180203] [PMID:  7839316] 
[101] 
Ahlskog, J.E.; Uitti, R.J. Rasagiline, Parkinson neuroprotection, and delayed-start trials: still no satisfaction? Neurology,  2010, 74(14), 1143-1148.
[http://dx.doi.org/http://10.1212/WNL.0b013e3181 d7d8e2] [PMID:  20368634] 
[102] 
Majbour, N.K.; Vaikath, N.N.; Eusebi, P.; Chiasserini, D.; Ardah, M.; Varghese, S.; Haque, M.E.; Tokuda, T.; Auinger, P.; Calabresi, P.; Parnetti, L.; El-Agnaf, O.M. Longitudinal changes in CSF alpha-synuclein species reflect Parkinson’s disease progression. Mov. Disord.,  2016, 31(10), 1535-1542.
[http://dx.doi.org/http://10.1002/mds. 26754] [PMID:  27548849] 
[103] 
Chiba, K.; Trevor, A.; Castagnoli, N., Jr Metabolism of the neurotoxic tertiary amine, MPTP, by brain monoamine oxidase. Biochem. Biophys. Res. Commun.,  1984, 120(2), 574-578.
[http://dx.doi.org/http://10.1016/0006-291X(84)91293-2] [PMID:  6428396] 
[104] 
Glover, V.; Gibb, C.; Sandler, M. Monoamine oxidase B(MAO-B) is the major catalyst for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) oxidation in human brain and other tissues. Neurosci. Lett.,  1986, 64(2), 216-220.
[http://dx.doi.org/http://10.1016/0304-3940 (86)90103-5] [PMID:  3083305] 
[105] 
Akos, K. MPTP, selegiline, and parkinsonism. Lancet,  1987, 1(8523), 38-39.
[http://dx.doi.org/http://10.1016/S0140-6736(87)90723-9] [PMID:  2879111] 
[106] 
Cohen, G.; Pasik, P.; Cohen, B.; Leist, A.; Mytilineou, C.; Yahr, M.D. Pargyline and deprenyl prevent the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys. Eur. J. Pharmacol.,  1984, 106(1), 209-210.
[http://dx.doi.org/http://10. 1016/0014-2999(84)90700-3] [PMID:  6442232] 
[107] 
Ebadi, M.; Sharma, S.; Shavali, S.; El Refaey, H. Neuroprotective actions of selegiline. J. Neurosci. Res.,  2002, 67(3), 285-289.
[http://dx.doi.org/http://10.1002/jnr.10148] [PMID:  11813232] 
[108] 
Fredriksson, A.; Palomo, T.; Archer, T. Effects of MAO inhibitors upon MPTP mice chronically treated with suprathreshold doses of L-dopa. Behav. Pharmacol.,  2000, 11(7-8), 571-581.
[http://dx.doi.org/http://dx.doi. org/10.1097/00008877-200011000-00004] [PMID:  11198128] 
[109] 
Fuller, R.W.; Hemrick-Luecke, S.K.; Perry, K.W. Deprenyl antagonizes acute lethality of 1-methyl-4-phenyl-1,2,3,6-tetrahydro- pyridine in mice. J. Pharmacol. Exp. Ther.,  1988, 247(2), 531-535.
[PMID:  3141609] 
[110] 
Gupta, M.; Wiener, H.L. Effects of deprenyl on monoamine oxidase and neurotransmitters in the brains of MPTP-treated aging mice. Neurochem. Res.,  1995, 20(4), 385-389.
[http://dx.doi.org/http:// 10.1007/BF00973091] [PMID:  7544444] 
[111] 
Heikkila, R.E.; Hess, A.; Duvoisin, R.C. Dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) in the mouse: relationships between monoamine oxidase, MPTP metabolism and neurotoxicity. Life Sci.,  1985, 36(3), 231-236.
[http://dx.doi.org/http://10.1016/0024-3205(85)90064-5] [PMID:  3917525] 
[112] 
Kupsch, A.; Sautter, J.; Götz, M.E.; Breithaupt, W.; Schwarz, J.; Youdim, M.B.; Riederer, P.; Gerlach, M.; Oertel, W.H. Monoamine oxidase-inhibition and MPTP-induced neurotoxicity in the non-human primate: comparison of rasagiline (TVP 1012) with selegiline. J. Neural Transm. (Vienna),  2001, 108(8-9), 985-1009.
[http://dx.doi.org/http://10.1007/s007020170018] [PMID:  11716151] 
[113] 
Muralikrishnan, D.; Samantaray, S.; Mohanakumar, K.P. D-deprenyl protects nigrostriatal neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity. Synapse,  2003, 50(1), 7-13.
[http://dx.doi.org/http://10.1002/syn.10239] [PMID:  12872288] 
[114] 
Sagi, Y.; Mandel, S.; Amit, T.; Youdim, M.B. Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism. Neurobiol. Dis.,  2007, 25(1), 35-44.
[http://dx.doi.org/http://10.1016/j.nbd.2006.07.020] [PMID:  17055733] 
[115] 
Tatton, W.G.; Greenwood, C.E. Rescue of dying neurons: A new action for deprenyl in MPTP parkinsonism. J. Neurosci. Res.,  1991, 30(4), 666-672.
[http://dx.doi.org/http://10.1002/jnr.490300410] [PMID:  1686284] 
[116] 
Wu, W.R.; Zhu, Z.T.; Zhu, X.Z. Differential effects of L-deprenyl on MPP+- and MPTP-induced dopamine overflow in microdialysates of striatum and nucleus accumbens. Life Sci.,  2000, 67(3), 241-250.
[http://dx.doi.org/http://10.1016/S0024-3205(00)00628-7] [PMID:  10983868] 
[117] 
Vizuete, M.L.; Steffen, V.; Ayala, A.; Cano, J.; Machado, A. Protective effect of deprenyl against 1-methyl-4-phenylpyridinium neurotoxicity in rat striatum. Neurosci. Lett.,  1993, 152(1-2), 113-116.
[http://dx.doi.org/http://10.1016/0304-3940(93)90496-8] [PMID:  8515861] 
[118] 
West, B.D.; Shughrue, P.J.; Vanko, A.E.; Ransom, R.W.; Kinney, G.G. Amphetamine-induced locomotor activity is reduced in mice following MPTP treatment but not following selegiline/MPTP treatment. Pharmacol. Biochem. Behav.,  2006, 84(1), 158-161.
[http://dx.doi.org/http://10.1016/j.pbb.2006.04.022] [PMID:  16757017] 
[119] 
Zhao, Q.; Cai, D.; Bai, Y. Selegiline rescues gait deficits and the loss of dopaminergic neurons in a subacute MPTP mouse model of Parkinson’s disease. Int. J. Mol. Med.,  2013, 32(4), 883-891.
[http://dx.doi.org/http://10.3892/ijmm.2013.1450] [PMID:  23877198] 
[120] 
Inaba-Hasegawa, K.; Shamoto-Nagai, M.; Maruyama, W.; Naoi, M. Type B and A monoamine oxidase and their inhibitors regulate the gene expression of Bcl-2 and neurotrophic factors in human glioblastoma U118MG cells: different signal pathways for neuroprotection by selegiline and rasagiline. J. Neural Transm. (Vienna),  2017, 124(9), 1055-1066.
[http://dx.doi.org/http://10.1007/s00702-017-1740-9] [PMID:  28577058] 
[121] 
Maruyama, W.; Naoi, M. “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),  2013, 120(1), 83-89.
[http://dx.doi.org/http://10.1007/s00702-012-0876-x] [PMID:  22892822] 
[122] 
Mandel, S.A.; Sagi, Y.; Amit, T. Rasagiline promotes regeneration of substantia nigra dopaminergic neurons in post-MPTP-induced Parkinsonism via activation of tyrosine kinase receptor signaling pathway. Neurochem. Res.,  2007, 32(10), 1694-1699.
[http://dx.doi.org/http://10.1007/s11064-007-9351-8] [PMID:  17701352] 
[123] 
Nagatsu, T.; Sawada, M. Molecular mechanism of the relation of monoamine oxidase B and its inhibitors to Parkinson’s disease: possible implications of glial cells. J. Neural Transm. Suppl.,  2006, (71), 53-65.
[PMID:  17447416] 
[124] 
Naoi, M.; Maruyama, W. Monoamine oxidase inhibitors as neuroprotective agents in age-dependent neurodegenerative disorders. Curr. Pharm. Des.,  2010, 16(25), 2799-2817.
[http://dx.doi.org/http://10. 2174/138161210793176527] [PMID:  20698822] 
[125] 
Naoi, M.; Maruyama, W.; Inaba-Hasegawa, K. Revelation in the neuroprotective functions of rasagiline and selegiline: the induction of distinct genes by different mechanisms. Expert Rev. Neurother.,  2013, 13(6), 671-684.
[http://dx.doi.org/http://10.1586/ern.13.60] [PMID:  23739004] 
[126] 
Kramer, E.R.; Liss, B. GDNF-Ret signaling in midbrain dopaminergic neurons and its implication for Parkinson disease. FEBS Lett.,  2015, 589(24 Pt A), 3760-3772.
[http://dx.doi.org/http://10.1016/j. febslet.2015.11.006] [PMID:  26555190] 
[127] 
Tenenbaum, L.; Humbert-Claude, M. Glial cell line-derived neurotrophic factor gene delivery in Parkinson’s Disease: A delicate balance between neuroprotection, trophic effects, and unwanted Compensatory mechanisms. Front. Neuroanat.,  2017, 11, 29.
[http://dx.doi.org/http://10.3389/fnana.2017.00029] [PMID:  28442998] 
[128] 
Gash, D.M.; Zhang, Z.; Gerhardt, G. Neuroprotective and neurorestorative properties of GDNF. Ann. Neurol.,  1998, 44(3)(Suppl. 1), S121-S125.
[http://dx.doi.org/http://10.1002/ana.410440718] [PMID:  9749583] 
[129] 
Kordower, J.H. In vivo gene delivery of glial cell line--derived neurotrophic factor for Parkinson’s disease. Ann. Neurol.,  2003, 53(Suppl. 3), S120-S132.
[http://dx.doi.org/http://10.1002/ana.10485] [PMID:  12666104] 
[130] 
Lin, L.F.; Doherty, D.H.; Lile, J.D.; Bektesh, S.; Collins, F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science,  1993, 260(5111), 1130-1132.
[http://dx.doi.org/http://10.1126/science.8493557] [PMID:  8493557] 
[131] 
Gill, S.S.; Patel, N.K.; Hotton, G.R.; O’Sullivan, K.; McCarter, R.; Bunnage, M.; Brooks, D.J.; Svendsen, C.N.; Heywood, P. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med.,  2003, 9(5), 589-595.
[http://dx.doi.org/http:// 10.1038/nm850] [PMID:  12669033] 
[132] 
Brouillet, E.; Beal, M.F. NMDA antagonists partially protect against MPTP induced neurotoxicity in mice. Neuroreport,  1993, 4(4), 387-390.
[http://dx.doi.org/http://10.1097/00001756-199304000-00011] [PMID:  8499594] 
[133] 
Lange, K.W.; Löschmann, P.A.; Sofic, E.; Burg, M.; Horowski, R.; Kalveram, K.T.; Wachtel, H.; Riederer, P. The competitive NMDA antagonist CPP protects substantia nigra neurons from MPTP-induced degeneration in primates. Naunyn Schmiedebergs Arch. Pharmacol.,  1993, 348(6), 586-592.
[http://dx.doi.org/http://10.1007/BF00167234] [PMID:  7907775] 
[134] 
Turski, L.; Bressler, K.; Rettig, K.J.; Löschmann, P.A.; Wachtel, H. Protection of substantia nigra from MPP+ neurotoxicity by N-methyl-D-aspartate antagonists. Nature,  1991, 349(6308), 414-418.
[http://dx.doi.org/http://10.1038/349414a0] [PMID:  1846943] 
[135] 
Battaglia, G.; Fornai, F.; Busceti, C.L.; Aloisi, G.; Cerrito, F.; De Blasi, A.; Melchiorri, D.; Nicoletti, F. Selective blockade of mGlu5 metabotropic glutamate receptors is protective against methamphetamine neurotoxicity. J. Neurosci.,  2002, 22(6), 2135-2141.
[http://dx.doi.org/http://10.1523/JNEUROSCI.22-06-02135.2002] [PMID:  11896153] 
[136] 
Battaglia, G.; Busceti, C.L.; Molinaro, G.; Biagioni, F.; Storto, M.; Fornai, F.; Nicoletti, F.; Bruno, V. Endogenous activation of mGlu5 metabotropic glutamate receptors contributes to the development of nigro-striatal damage induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. J. Neurosci.,  2004, 24(4), 828-835.
[http://dx.doi.org/http://10.1523/JNEUROSCI.3831-03.2004] [PMID:  14749427] 
[137] 
Masilamoni, G.J.; Bogenpohl, J.W.; Alagille, D.; Delevich, K.; Tamagnan, G.; Votaw, J.R.; Wichmann, T.; Smith, Y. Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. Brain,  2011, 134(Pt 7), 2057-2073.
[http://dx.doi.org/http:// 10.1093/brain/awr137] [PMID:  21705423] 
[138] 
Muñoz-Manchado, A.B.; Villadiego, J.; Romo-Madero, S.; Suárez-Luna, N.; Bermejo-Navas, A.; Rodríguez-Gómez, J.A.; Garrido-Gil, P.; Labandeira-García, J.L.; Echevarría, M.; López-Barneo, J.; Toledo-Aral, J.J. Chronic and progressive Parkinson’s disease MPTP model in adult and aged mice. J. Neurochem.,  2016, 136(2), 373-387.
[http://dx.doi.org/http://10.1111/jnc.13409] [PMID:  26500044] 
[139] 
Tozzi, A.; Tantucci, M.; Marchi, S.; Mazzocchetti, P.; Morari, M.; Pinton, P.; Mancini, A.; Calabresi, P. Dopamine D2 receptor-mediated neuroprotection in a G2019S Lrrk2 genetic model of Parkinson’s disease. Cell Death Dis.,  2018, 9(2), 204.
[http://dx.doi.org/http://10.1038/s41419-017-0221-2] [PMID:  29434188] 
Rights & Permissions Print Cite
Article Metrics
82
6
1
2
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1570159X16666180830100754	Print ISSN 1570-159X
Publisher Name Bentham Science Publisher	Online ISSN 1875-6190
Current Neuropharmacology

Different Generations of Type-B Monoamine Oxidase Inhibitors in Parkinson’s Disease: From Bench to Bedside

Abstract

Graphical Abstract

Related Journals

Related Books

Related Articles
