JM-20, a Benzodiazepine-Dihydropyridine Hybrid Molecule, Inhibits the Formation of Alpha-Synuclein-Aggregated Species.

Autor: Santos CC; Laboratory of Neurochemistry and Cell Biology, Department of Biochemistry and Biophysics, Federal University of Bahia - Institute of Health Sciences, Salvador, 40110-100, Brazil., Cardim-Pires TR; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Shvachiy L; Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Gottingen, Göttingen, Germany.; Faculdade de Medicina, Centro Cardiovascular da Universidade de Lisboa, Universidade de Lisboa, Av Prof Egas Moniz, 1649-028, Lisbon, Portugal., Fonseca-Fonseca LA; Centro de Investigación y Desarrollo de Medicamentos (CIDEM), La Habana, Cuba., Muñoz P; Instituto de Ciencias Biomedicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile., Almeida ÁMAN; Laboratory of Neurochemistry and Cell Biology, Department of Biochemistry and Biophysics, Federal University of Bahia - Institute of Health Sciences, Salvador, 40110-100, Brazil., Costa ACS; Laboratory of Neurochemistry and Cell Biology, Department of Biochemistry and Biophysics, Federal University of Bahia - Institute of Health Sciences, Salvador, 40110-100, Brazil., Teles-Souza J; Laboratory of Neurochemistry and Cell Biology, Department of Biochemistry and Biophysics, Federal University of Bahia - Institute of Health Sciences, Salvador, 40110-100, Brazil., Ochoa-Rodríguez E; Organic Synthesis Laboratory of the Faculty of Chemistry of the University of Havana, Havana, Cuba., de Fátima Dias Costa M; Laboratory of Neurochemistry and Cell Biology, Department of Biochemistry and Biophysics, Federal University of Bahia - Institute of Health Sciences, Salvador, 40110-100, Brazil., Palhano FL; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Segura-Aguilar J; Molecular & Clinical Pharmacology, Faculty of Medicine, ICBM, University of Chile, Santiago, Chile., Barbosa DB; Laboratory of Molecular Modeling, Department of Health, State University of Feira de Santana, Feira de Santana, Brazil., do Bomfim MR; Laboratory of Molecular Modeling, Department of Health, State University of Feira de Santana, Feira de Santana, Brazil., Dos Santos Junior MC; Laboratory of Molecular Modeling, Department of Health, State University of Feira de Santana, Feira de Santana, Brazil., Leite FHA; Laboratory of Molecular Modeling, Department of Health, State University of Feira de Santana, Feira de Santana, Brazil., da Rocha Pita SS; Bioinformatics and Molecular Modeling Laboratory (LaBiMM), Federal University of Bahia - College of Pharmacy, Salvador, Brazil., Costa SL; Laboratory of Neurochemistry and Cell Biology, Department of Biochemistry and Biophysics, Federal University of Bahia - Institute of Health Sciences, Salvador, 40110-100, Brazil., Núñez-Figueredo Y; Centro de Investigación y Desarrollo de Medicamentos (CIDEM), La Habana, Cuba., Outeiro TF; Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Gottingen, Göttingen, Germany.; Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany.; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK.; Scientific Employee With an Honorary Contract at German Center for Neurodegenerative Diseases (DZNE), 37075, Göttingen, Germany., Foguel D; Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil., Silva VDA; Laboratory of Neurochemistry and Cell Biology, Department of Biochemistry and Biophysics, Federal University of Bahia - Institute of Health Sciences, Salvador, 40110-100, Brazil. vdsilva@ufba.br.
Jazyk: angličtina
Zdroj: Neurotoxicity research [Neurotox Res] 2022 Dec; Vol. 40 (6), pp. 2135-2147. Date of Electronic Publication: 2022 Aug 23.
DOI: 10.1007/s12640-022-00559-7
Abstrakt: Studies showed that JM-20, a benzodiazepine-dihydropyridine hybrid molecule, protects against rotenone and 6-hydroxydopamine neurotoxicity. However, its protective effects against cytotoxicity induced by endogenous neurotoxins involved in Parkinson's disease (PD) pathogenesis have never been investigated. In this study, we evaluated the ability of JM-20 to inhibit alpha-synuclein (aSyn) aggregation. We also evaluated the interactions of JM-20 with aSyn by molecular docking and molecular dynamics and assessed the protective effect of JM-20 against aminochrome cytotoxicity. We demonstrated that JM-20 induced the formation of heterogeneous amyloid fibrils, which were innocuous to primary cultures of mesencephalic cells. Moreover, JM-20 reduced the average size of aSyn positive inclusions in H4 cells transfected with SynT wild-type and synphilin-1-V5, but not in HEK cells transfected with synphilin-1-GFP. In silico studies showed the interaction between JM-20 and the aSyn-binding site. Additionally, we showed that JM-20 protects SH-SY5Y cells against aminochrome cytotoxicity. These results reinforce the potential of JM-20 as a neuroprotective compound for PD and suggest aSyn as a molecular target for JM-20.
(© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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