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

A novel NMR-based assay to measure circulating concentrations of branched-chain amino acids:Elevation in subjects with type 2 diabetes mellitus and association with carotid intima media thickness

OBJECTIVES: Plasma branched-chain amino acid (BCAA) levels, measured on nuclear magnetic resonance (NMR) metabolomics research platforms or by mass spectrometry, have been shown to be associated with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). We developed a new test for quantification of BCAA on a clinical NMR analyzer and used this test to determine the clinical correlates of BCAA in 2 independent cohorts. DESIGN AND METHODS: The performance of the NMR-based BCAA assay was evaluated. A method comparison study was performed with mass spectrometry (LC-MS/MS). Plasma BCAA were measured in the Insulin Resistance Atherosclerosis Study (IRAS, n = 1209; 376 T2DM subjects) and in a Groningen cohort (n = 123; 67 T2DM subjects). In addition, carotid intima media thickness (cIMT) was measured successfully in 119 subjects from the Groningen cohort. RESULTS: NMR-based BCAA assay results were linear over a range of concentrations. Coefficients of variation for inter- and intra-assay precision ranged from 1.8-6.0, 1.7-5.4, 4.4-9.1, and 8.8-21.3%, for total BCAA, valine, leucine, and isoleucine, respectively. BCAA quantified from the same samples using NMR and LC-MS/MS were highly correlated (R2 = 0.97, 0.95 and 0.90 for valine, leucine and isoleucine). In both cohorts total and individual BCAA were elevated in T2DM (P = 0.01 to ≤0.001). Moreover, cIMT was associated with BCAA independent of age, sex, T2DM and metabolic syndrome (MetS) categorization or alternatively of individual MetS components. CONCLUSIONS: BCAA levels, measured by NMR in the clinical laboratory, are elevated in T2DM and may be associated with cIMT, a proxy of subclinical atherosclerosis

QSAR studies on a number of pyrrolidin-2-one antiarrhythmic arylpiperazinyls

The activity of a number of 1-[3-(4-arylpiperazin-1-yl)propyl]pyrrolidin-2-one antiarrhythmic (AA) agents was described using the quantitative structure–activity relationship model by applying it to 33 compounds. The molecular descriptors of the AA activity were obtained by quantum chemical calculations combined with molecular modeling calculations. The resulting model explains up to 91% of the variance and it was successfully validated by four tests (LOO, LMO, external test, and Y-scrambling test). Statistical analysis shows that the AA activity of the studied compounds depends mainly on the PCR and JGI4 descriptors

Antiarrhythmic and antioxidant activity of novel pyrrolidin-2-one derivatives with adrenolytic properties

A series of novel pyrrolidin-2-one derivatives (17 compounds) with adrenolytic properties was evaluated for antiarrhythmic, electrocardiographic and antioxidant activity. Some of them displayed antiarrhythmic activity in barium chloride-induced arrhythmia and in the rat coronary artery ligation-reperfusion model, and slightly decreased the heart rate, prolonged P–Q, Q–T intervals and QRS complex. Among them, compound EP-40 (1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one showed excellent antiarrhythmic activity. This compound had significantly antioxidant effect, too. The present results suggest that the antiarrhythmic effect of compound EP-40 is related to their adrenolytic and antioxidant properties. A biological activity prediction using the PASS software shows that compound EP-35 and EP-40 can be characterized by antiischemic activity; whereas, compound EP-68, EP-70, EP-71 could be good tachycardia agents

The SECOQC quantum key distribution network in Vienna

In this paper, we present the quantum key distribution (QKD) network designed and implemented by the European project SEcure COmmunication based on Quantum Cryptography (SECOQC) (2004–2008), unifying the efforts of 41 research and industrial organizations. The paper summarizes the SECOQC approach to QKD networks with a focus on the trusted repeater paradigm. It discusses the architecture and functionality of the SECOQC trusted repeater prototype, which has been put into operation in Vienna in 2008 and publicly demonstrated in the framework of a SECOQC QKD conference held from October 8 to 10, 2008. The demonstration involved one-time pad encrypted telephone communication, a secure (AES encryption protected) video-conference with all deployed nodes and a number of rerouting experiments, highlighting basic mechanisms of the SECOQC network functionality.The paper gives an overview of the eight point-to-point network links in the prototype and their underlying technology: three plug and play systems by id Quantique, a one way weak pulse system from Toshiba Research in the UK, a coherent one-way system by GAP Optique with the participation of id Quantique and the AIT Austrian Institute of Technology (formerly ARCAustrian Research Centers GmbH—ARC is now operating under the new name AIT Austrian Institute of Technology GmbH following a restructuring initiative.), an entangled photons system by the University of Vienna and the AIT, a continuous-variables system by Centre National de la Recherche Scientifique (CNRS) and THALES Research and Technology with the participation of Université Libre de Bruxelles, and a free space link by the Ludwig Maximillians University in Munich connecting two nodes situated in adjacent buildings (line of sight 80 m). The average link length is between 20 and 30 km, the longest link being 83 km.The paper presents the architecture and functionality of the principal networking agent—the SECOQC node module, which enables the authentic classical communication required for key distillation, manages the generated key material, determines a communication path between any destinations in the network, and realizes end-to-end secure transport of key material between these destinations.The paper also illustrates the operation of the network in a number of typical exploitation regimes and gives an initial estimate of the network transmission capacity, defined as the maximum amount of key that can be exchanged, or alternatively the amount of information that can be transmitted with information theoretic security, between two arbitrary nodes