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

1 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. [email protected].
2 Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy. [email protected].
3 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. [email protected].
4 János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary. [email protected].
5 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. [email protected].
6 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. [email protected].
7 János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary. [email protected].
8 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. [email protected].
9 National Research Council of Italy, Neuroscience Institute, Cagliari, Italy. [email protected].
10 Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy. [email protected].
11 Institute of Chemical Engineering and Science, A*STAR, 8 Biomedical Grove, Neuros, Singapore, 138665, Singapore. [email protected].
12 Institute of Chemical Engineering and Science, A*STAR, 8 Biomedical Grove, Neuros, Singapore, 138665, Singapore. [email protected].
13 Institute of Chemical Engineering and Science, A*STAR, 8 Biomedical Grove, Neuros, Singapore, 138665, Singapore. [email protected].
14 Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore. [email protected].
15 Institute of Organic Chemistry, Semmelweis University, Budapest, Hungary. [email protected].
16 Institute of Organic Chemistry, Semmelweis University, Budapest, Hungary. [email protected].
17 Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy. [email protected].
18 National Research Council of Italy, Neuroscience Institute, Cagliari, Italy. [email protected].
19 Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary. [email protected].

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.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-123556

SZV-558

MAO-B Inhibitor

Monoamine Oxidase

Neurological Disease

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