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

Abstract

BackgroundMitochondrial 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.ResultsThe (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.ConclusionsSimultaneous 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-015-0067-y) contains supplementary material, which is available to authorized users.

Optimization and validation of online column-switching assisted HPLC-spectrometric method for quantification of dansylated endocannabinoids and neurotransmitters in animal models of brain diseases

“…Changes in the concentration of neurotransmitters-such as dopamine, glutamate, GABA, anandamide and 2-AG -are shown in Tables 4,5. The acute MPTP treatment signifi cantly reduced the striatal dopamine content (F1,35=943.54; p<0.000001) when compared to the salt treated mice, and this effect was independent of the genotype of the mice and was consistent with our previous fi ndings [37]. However, when comparing the rate of dopamine reduction, the MPTP effect was signifi cantly lower in subacute treated and in P 2 Y 12 receptor defi cient animals.…”

“…We have also evaluated the effi cacy of novel (hetero)aryl alkenyl propargylamine compounds in MPTP-induced acute and subacute mouse models of PD [37]. Endocannabinoids primarily act in retrograde, facilitating short-and longterm plasticity, both at excitatory and inhibitory synapses, while also interacting with the dopaminergic system [38].…”

Manganese‐Catalyzed Multicomponent Synthesis of Tetrasubstituted Propargylamines: System Development and Theoretical Study

“…[1,2] The biological activity of various members of their family renders them inherently valuable in drug development, mostly against neurodegenerative diseases. [1][2][3][4][5][6][7][8][9] In addition, propargylic amines are useful building blocks in organic synthesis, providing access to diverse molecular architectures. [1,2] The unique structure of these compounds is based on the existence of an amine group in β-position to an alkyne moiety, which leads to diverse reactivity.…”

Roles Played by the Na+/Ca2+ Exchanger and Hypothermia in the Prevention of Ischemia-Induced Carrier-Mediated Efflux of Catecholamines into the Extracellular Space: Implications for Stroke Therapy

“…Thus, during ischemia, when dopaminergic axon terminals are energy compromised the resting, non-vesicular release of DA is accelerated. The occurence of neurotoxic DA metabolites (DOPAL and quinone) in the perfusate indicates that they play roles in neuronal toxicity [133,136,137].…”