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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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Identification of a compound that promotes synaptic function and ameliorates cognition deficits in APP/PS1 transgenic mice

Identification of a compound that promotes synaptic function...

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中国神经科学学会第十二届全国学术会议

作者： Xiaoji Zhuang Yumei Liao Xuan-Yue Ma Xiaojie Huang Yinghui Peng Lei Shi JNU-HKUST Joint Laboratory for Neuroscience and Innovative Drug Research Jinan University

objective Alzheimer’s disease（AD） is a neurodegenerative disease characterized by progressive memory dysfunction and increasingly severe dementia. The most widely accepted hypothesis is that aggregation of β-amyloid（Aβ） leads to a series of devastating effects to the nervous system, such as synaptic failure and neuronal death. The current drug development for AD therapy is mainly designed to antagonize Aβ, but the effect on cognition would be limited if the synaptic function is not restored. It is recently found that protein synthesis（m RNA translation） is impaired in AD brain, which leads to insufficient synthesis of critical proteins for synaptic function and neuronal survival. Therefore, identification of compounds that has the ability to enhance protein synthesis in neurons will be beneficial for the restoration of synaptic function and memory in AD. We previously found a compound C6, which induces robust protein synthesis in neuronal cell lines. This study aims to test whether this compound promotes synaptic function in hippocampal neurons, and whether it restores the synaptic and memory defects in AD modeled mice. Methods A puromycin labeling method was performed to test protein synthesis;Immunofluorescence and western-blot were used to test the expression of synaptic proteins;APP/PS1 transgenic mice, a widely accepted mouse model of AD, was used to test the treatment effect of C6;Novel object recognition test was used to test learning and memory of the mice. Results（1） C6 promoted de novo protein synthesis in hippocampal neurons;（2） C6 increased the expression of synapsin I and PSD95;（3） C6 promoted dendritic spine formation in hippocampal neurons which depended on translation;（4） C6 improved Novel object recognition in APP/PS1 mice. Conclusion C6, through upregulating protein synthesis, promotes synaptic function in cultured neurons and restores cognition functions in APP/PS1 mice.

关键词： Alzheimer’s disease protein synthesis dendritic spines synapse Novel object recognition

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