title: Novel (Hetero)arylalkenyl propargylamine compounds are protective in toxin-induced models of Parkinson's disease.
abstract: BACKGROUND
  Mitochondrial dysfunction, oxidative stress and their interplay are core pathological features of Parkinson's disease. In dopaminergic neurons, monoamines and their metabolites provide an additional source of reactive free radicals during their breakdown by monoamine oxidase or auto-oxidation. Moreover, mitochondrial dysfunction and oxidative stress have a supraadditive impact on the pathological, cytoplasmic accumulation of dopamine and its subsequent release. Here we report the effects of a novel series of potent and selective MAO-B inhibitory (hetero)arylalkenylpropargylamine compounds having protective properties against the supraadditive effect of mitochondrial dysfunction and oxidative stress.
  
  
  RESULTS
  The (hetero)arylalkenylpropargylamines were tested in vitro, on acute rat striatal slices, pretreated with the complex I inhibitor rotenone and in vivo, using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced acute, subchronic, and chronic experimental models of Parkinson's disease in mice. The compounds exhibited consistent protective effects against i) in vitro oxidative stress induced pathological dopamine release and the formation of toxic dopamine quinone in the rat striatum and rescued tyrosine hydroxylase positive neurons in the substantia nigra after rotenone treatment; ii) in vivo MPTP-induced striatal dopamine depletion and motor dysfunction in mice using acute and subchronic, delayed application protocols. One compound (SZV558) was also examined and proved to be protective in a chronic mouse model of MPTP plus probenecid (MPTPp) administration, which induces a progressive loss of nigrostriatal dopaminergic neurons.
  
  
  CONCLUSIONS
  Simultaneous inhibition of MAO-B and oxidative stress induced pathological dopamine release by the novel propargylamines is protective in animal models and seems a plausible strategy to combat Parkinson's disease.
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. baranyi@koki.hu.
authors.forename: Mária
authors.initials: M
authors.lastname: Baranyi
authors.affiliation: Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy. p.f.porceddu@gmail.com.
authors.forename: Pier Francesca
authors.initials: PF
authors.lastname: Porceddu
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. goloncser.flora@koki.mta.hu.|János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary. goloncser.flora@koki.mta.hu.
authors.forename: Flóra
authors.initials: F
authors.lastname: Gölöncsér
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. kulcsar.szabina@tdk.koki.mta.hu.
authors.forename: Szabina
authors.initials: S
authors.lastname: Kulcsár
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. otrokocsi.lilla@koki.mta.hu.|János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary. otrokocsi.lilla@koki.mta.hu.
authors.forename: Lilla
authors.initials: L
authors.lastname: Otrokocsi
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. kittel@koki.hu.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Kittel
authors.affiliation: National Research Council of Italy, Neuroscience Institute, Cagliari, Italy. apinna@unica.it.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pinna
authors.affiliation: Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy. lfrau@unica.it.
authors.forename: Lucia
authors.initials: L
authors.lastname: Frau
authors.affiliation: Institute of Chemical Engineering and Science, A*STAR, 8 Biomedical Grove, Neuros, Singapore, 138665, Singapore. paul_huleatt@ices.a-star.edu.sg.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Huleatt
authors.affiliation: Institute of Chemical Engineering and Science, A*STAR, 8 Biomedical Grove, Neuros, Singapore, 138665, Singapore. khoo_mui_ling@ices.a-star.edu.sg.
authors.forename: Mui-Ling
authors.initials: ML
authors.lastname: Khoo
authors.affiliation: Institute of Chemical Engineering and Science, A*STAR, 8 Biomedical Grove, Neuros, Singapore, 138665, Singapore. phacllc@nus.edu.sg.|Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore. phacllc@nus.edu.sg.
authors.forename: Christina L L
authors.initials: CL
authors.lastname: Chai
authors.affiliation: Institute of Organic Chemistry, Semmelweis University, Budapest, Hungary. dunkel.petra@pharma.semmelweis-univ.hu.
authors.forename: Petra
authors.initials: P
authors.lastname: Dunkel
authors.affiliation: Institute of Organic Chemistry, Semmelweis University, Budapest, Hungary. matyus.peter@pharma.semmelweis-univ.hu.
authors.forename: Peter
authors.initials: P
authors.lastname: Mátyus
authors.affiliation: Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy. morelli@unica.it.|National Research Council of Italy, Neuroscience Institute, Cagliari, Italy. morelli@unica.it.
authors.forename: Micaela
authors.initials: M
authors.lastname: Morelli
authors.affiliation: Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. sperlagh@koki.hu.
authors.forename: Beáta
authors.initials: B
authors.lastname: Sperlágh
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010293:Pargyline / Q000031:analogs & derivatives* / Q000494:pharmacology; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011437:Propylamines / Q000494:pharmacology*; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D011437:Propylamines; C009054:propargylamine; C104705:dopamine quinone; D010293:Pargyline; D004298:Dopamine