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.
