2. Academic Validation
  3. Novel (Hetero)arylalkenyl propargylamine compounds are protective in toxin-induced models of Parkinson's disease

Novel (Hetero)arylalkenyl propargylamine compounds are protective in toxin-induced models of Parkinson's disease

  • Mol Neurodegener. 2016 Jan 13:11:6. doi: 10.1186/s13024-015-0067-y.
Mária Baranyi 1,  Pier Francesca Porceddu 2,  Flóra Gölöncsér 3 4,  Szabina Kulcsár 5,  Lilla Otrokocsi 6 7,  Ágnes Kittel 8,  Annalisa Pinna 9,  Lucia Frau 10,  Paul B Huleatt 11,  Mui-Ling Khoo 12,  Christina L L Chai 13 14,  Petra Dunkel 15,  Peter Mátyus 16,  Micaela Morelli 17 18,  Beáta Sperlágh 19
Affiliations

Affiliations

  • 1 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. baranyi@koki.hu.
  • 2 Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy. p.f.porceddu@gmail.com.
  • 3 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. goloncser.flora@koki.mta.hu.
  • 4 János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary. goloncser.flora@koki.mta.hu.
  • 5 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. kulcsar.szabina@tdk.koki.mta.hu.
  • 6 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. otrokocsi.lilla@koki.mta.hu.
  • 7 János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary. otrokocsi.lilla@koki.mta.hu.
  • 8 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. kittel@koki.hu.
  • 9 National Research Council of Italy, Neuroscience Institute, Cagliari, Italy. apinna@unica.it.
  • 10 Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy. lfrau@unica.it.
  • 11 Institute of Chemical Engineering and Science, A*STAR, 8 Biomedical Grove, Neuros, Singapore, 138665, Singapore. paul_huleatt@ices.a-star.edu.sg.
  • 12 Institute of Chemical Engineering and Science, A*STAR, 8 Biomedical Grove, Neuros, Singapore, 138665, Singapore. khoo_mui_ling@ices.a-star.edu.sg.
  • 13 Institute of Chemical Engineering and Science, A*STAR, 8 Biomedical Grove, Neuros, Singapore, 138665, Singapore. phacllc@nus.edu.sg.
  • 14 Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore. phacllc@nus.edu.sg.
  • 15 Institute of Organic Chemistry, Semmelweis University, Budapest, Hungary. dunkel.petra@pharma.semmelweis-univ.hu.
  • 16 Institute of Organic Chemistry, Semmelweis University, Budapest, Hungary. matyus.peter@pharma.semmelweis-univ.hu.
  • 17 Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy. morelli@unica.it.
  • 18 National Research Council of Italy, Neuroscience Institute, Cagliari, Italy. morelli@unica.it.
  • 19 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. sperlagh@koki.hu.
PMID: 26758813 DOI: 10.1186/s13024-015-0067-y
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.

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