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

Molecular Neurodegeneration

Beáta Sperlágh²  Micaela Morelli⁶  Peter Mátyus¹  Petra Dunkel¹  Christina L. L. Chai⁷  Mui-Ling Khoo³  Paul B. Huleatt³  Lucia Frau⁴  Annalisa Pinna⁶  Ágnes Kittel²  Lilla Otrokocsi⁵  Szabina Kulcsár²  Flóra Gölöncsér⁵  Pier Francesca Porceddu⁴  Mária Baranyi² 

[1] Institute of Organic Chemistry, Semmelweis University, Budapest, Hungary;Laboratory of Molecular Pharmacology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary;Institute of Chemical Engineering and Science, A*STAR, 8 Biomedical Grove, Neuros, Singapore 138665, Singapore;Department of Biomedical Sciences, Section of Neuropsychopharmacology, University of Cagliari, Cagliari, Italy;János Szentágothai Doctoral School of Neurosciences, Semmelweis University, Budapest, Hungary;National Research Council of Italy, Neuroscience Institute, Cagliari, Italy;Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore

关键词: Dopamine;    Neuroprotection;    Mono-aminooxidase B;    Mitochondrial dysfunction;    Parkinson’s disease;    Propargylamine;   

Others  :  1235369
DOI  :  10.1186/s13024-015-0067-y

 received in 2015-08-25, accepted in 2015-12-22,  发布年份 2016

【 摘 要 】

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.

【 授权许可】

   
2016 Baranyi et al.

【 图 表 】

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