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

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

The multiple properties of gliotoxin and other epipolythiodioxopiperazine metabolites

10.1071/CH14482Australian Journal of Chemistry682178-18

Purification of Laboratory Chemicals

Purification of Laboratory Chemicals

A pattern recognition approach to 14-epi-hydrophenanthrene core of the morphine alkaloids based on shikimic acid

10.1016/j.tet.2011.03.063Tetrahedron67193363-3368TETR

Bidentate inhibitors of protein tyrosine phosphatases

10.1089/ars.2013.5710Antioxidants and Redox Signaling20142225-2250ARSI

N-Heterocyclic Carbene (NHC) Catalyzed Cycloaddition of CO 2 to N-Tosyl Aziridines: Regio and Stereoselective Synthesis of Oxazolidin-2-ones

10.1002/cctc.201200080ChemCatChem46774-77

Atom transfer radical polymerization (ATRP) of methyl methacrylate mediated by iron(II) chloride in the presence of polyethers as both solvents and ligands

10.1007/s13233-012-0077-3Macromolecular Research206552-55

Scope of direct arylation of fluorinated aromatics with aryl sulfonates

10.1039/c2ob06840kOrganic and Biomolecular Chemistry10112289-2299OBCR

Searching for "Environmentally-Benign" antifouling biocides

10.3390/ijms15069255International Journal of Molecular Sciences1569255-928

PolyPEGA with predetermined molecular weights from enzyme-mediated radical polymerization in water

10.1039/c1cc10989hChemical Communications47226464-6466CHCO