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8-Hydroxyquinolylnitrones as multifunctional ligands for the therapy of neurodegenerative diseases

Acta Pharmaceutica Sinica B 2023年第5期13卷 2152-2175页

作者： Damijan Knez Daniel Diez-Iriepa Mourad Chioua Andrea Gottinger Milica Denic Fabien Chantegreil Florian Nachon Xavier Brazzolotto Anna Skrzypczak-Wiercioch Ane Meden Anja Pilar Janko Kos Simon akelj Jure Stojan Kinga Saat Julia Serrano Ana Patricia Fernández Aitana Sánchez-García Ricardo Martínez-Murillo Claudia Binda Francisco López-Muoz Stanislav Gobec JoséMarco-Contelles University of Ljubljana Faculty of PharmacyLjubljana 1000Slovenia Laboratory of Medicinal Chemistry(Institute of Organic Chemistry CSIC)Madrid 28006Spain Departamento de Química Orgánicay Química Inorgánica Alcaláde HenaresMadrid 28871Spain Department of Biology and Biotechnology University of PaviaPavia 27100Italy Département de Toxicologie et Risques Chimiques Institut de Recherche Biomédicale des ArméesParis 91220France Department of Animal Anatomy and Preclinical Sciences University Centre of Veterinary Medicine JU-UAUniversity of Agriculture in KrakowKrakow 30-059Poland Institute of Biochemistry Faculty of MedicineUniversity of LjubljanaLjubljana 1000Slovenia Department of Pharmacodynamics Chair of PharmacodynamicsFaculty of PharmacyJagiellonian University Medical CollegeKrakow 30-688Poland Department of Translational Neurobiology Neurovascular Research GroupCajal Institute(CSIC)Madrid 28002Spain Biotechnology and Vegetal Biology Department Escuela Técnica Superior de Ingeniería AgronómicaAlimentaria y de BiosistemasUniversidad Politécnica de MadridMadrid 28040Spain Faculty of Health Camilo JoséCela University of Madrid(UCJC)Neuropsychopharmacology Unit“Hospital 12 de Octubre”Research InstituteMadrid 28692Spain

We describe the development of quinolylnitrones(QNs)as multifunctional ligands inhibiting cholinesterases(ChEs:acetylcholinesterase and butyrylcholinesterase—h BChE)and monoamine oxidases(hMAO-A/B)for the therapy of neurodegenerative diseases.We identified QN 19,a simple,low molecular weight nitrone,that is readily synthesized from commercially available 8-hydroxyquinoline-2-carbaldehyde.Quinolylnitrone 19 has no typical pharmacophoric element to suggest ChE or MAO inhibition,yet unexpectedly showed potent inhibition of h BChE(IC50=1.06±0.31 nmol/L)and h MAO-B(IC_(50)=4.46±0.18μmol/L).The crystal structures of 19 with hBChE and hMAO-B provided the structural basis for potent binding,which was further studied by enzyme kinetics.Compound 19 acted as a free radical scavenger and biometal chelator,crossed the blood—brain barrier,was not cytotoxic,and showed neuroprotective properties in a 6-hydroxydopamine cell model of Parkinson's disease.In addition,in vivo studies showed the anti-amnesic effect of 19 in the scopolamine-induced mouse model of AD without adverse effects on motoric function and coordination.Importantly,chronic treatment of double transgenic APPswe-PS1δE9 mice with 19 reduced amyloid plaque load in the hippocampus and cortex of female mice,underscoring the disease-modifying effect of QN 19.

关键词： Quinolylnitrone Butyrylcholinesterase Monoamine oxidase B Alzheimer's disease Multifunctional ligands 6-Hydroxydopamine model Passive avoidance task Novel object recognition

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Happy together？ Avoidance of conspecifics by gregarious mussels

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Current Zoology 2018年第1期64卷 53-61页

作者： anna DZIERZYNSKA-BIALONCZYK Aleksandra skrzypczak Jaroslaw KOBAK Faculty of Biology and Environmental Protection Department of Invertebrate Zoology Nicolaus CopernicusUniversity Lwowska 1 Torun 87-100 Poland

Zebra mussel Dreissena polymorpha is a Ponto-Caspian species invasive in Europe and North America, with great environmental impact. It lives byssally attached to hard substrata in large aggregations, which is often explained by its preferences for conspecifics, though direct evidence for such preferences has been rather limited so far. We studied the reactions of zebra mussels to conspecifics, hypothesizing that they may either be attracted to one another or form aggregations only in the absence of alternative attachment sites. In Experiment 1, we tested mussel tendency to detach from existing druses depending on druse size (2-25 individuals) and substratum type (soft: sand; hard: glass). Mussels detached significantly more often on the hard substratum and from larger druses compared to soft substratum and smaller druses, respectively. This indicates that mussels tended to avoid conspecifics at high density, particularly when alternative substratum was available. In Experiment 2, we tested the responses of single mussels to distant (3 or 15 cm) conspecifics (0, 3, 15 individuals per 2.5 l tank) on the sandy substratum. The presence of conspecifics, regardless of their distance and density, resulted in single unattached mussels staying more often in their initial positions. Mussels did not move preferentially towards or away from the conspecifics. Thus, even on unsuitable substratum mussels were not attracted by conspecifics and probably exhibited an avoidance reaction by reducing their movement. This suggests that dense mussel aggregations are formed due to the lack of available alternative attachment sites rather than due to their preferences for conspecifics.

关键词：回避反应贻贝基础类型群居环境影响高密度晶簇北美洲

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