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

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Abstract

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.

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Data Availability

The datasets used and analyzed in this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We are grateful to the postgraduate program in immunology at the Federal University of Bahia.

Funding

CCS, SLC, and JSA were supported by grants from the Coordenação de Apoio de Pessoal de Nível Superior (CAPES/PVE – 189576/09–2014); VDAS and SLC were supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ Edital Universal/2018 – 429127/2018–9 and Research fellowship). In silico research project (project ID: proj651) was developed with the help of CENAPAD-SP (National Center for High Performance Computing in São Paulo), UNICAMP/FINEP – MCT. LS was supported by Fundação para Ciência e Tecnologia (SFRH/BD/143286/2019). TFO was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy (EXC 2067/1 – 390729940) and by SFB1286 (Project B8).

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Author notes

  1. Cleonice Creusa Santos and Thyago R. Cardim-Pires have contributed equally to this paper.

Authors and Affiliations

  1. Laboratory of Neurochemistry and Cell Biology, Department of Biochemistry and Biophysics, Federal University of Bahia - Institute of Health Sciences, Salvador, 40110-100, Brazil

    Cleonice Creusa Santos, Áurea Maria A. N. Almeida, Ana Carla S. Costa, Jéssica Teles-Souza, Maria de Fátima Dias Costa, Silvia Lima Costa & Victor Diogenes Amaral Silva

  2. Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

    Thyago R. Cardim-Pires, Fernando L. Palhano & Débora Foguel

  3. Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Gottingen, Göttingen, Germany

    Liana Shvachiy & Tiago Fleming Outeiro

  4. Faculdade de Medicina, Centro Cardiovascular da Universidade de Lisboa, Universidade de Lisboa, Av Prof Egas Moniz, 1649-028, Lisbon, Portugal

    Liana Shvachiy

  5. Centro de Investigación y Desarrollo de Medicamentos (CIDEM), La Habana, Cuba

    Luis Arturo Fonseca-Fonseca & Yanier Núñez-Figueredo

  6. Instituto de Ciencias Biomedicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago, Chile

    Patricia Muñoz

  7. Organic Synthesis Laboratory of the Faculty of Chemistry of the University of Havana, Havana, Cuba

    Estael Ochoa-Rodríguez

  8. Molecular & Clinical Pharmacology, Faculty of Medicine, ICBM, University of Chile, Santiago, Chile

    Juan Segura-Aguilar

  9. Laboratory of Molecular Modeling, Department of Health, State University of Feira de Santana, Feira de Santana, Brazil

    Deyse B. Barbosa, Mayra R. do Bomfim, Manoelito C. dos Santos Junior & Franco Henrique A. Leite

  10. Bioinformatics and Molecular Modeling Laboratory (LaBiMM), Federal University of Bahia - College of Pharmacy, Salvador, Brazil

    Samuel Silva da Rocha Pita

  11. Max Planck Institute for Multidisciplinary Sciences, Goettingen, Germany

    Tiago Fleming Outeiro

  12. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK

    Tiago Fleming Outeiro

  13. Scientific Employee With an Honorary Contract at German Center for Neurodegenerative Diseases (DZNE), 37075, Göttingen, Germany

    Tiago Fleming Outeiro

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  1. Cleonice Creusa Santos
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  22. Victor Diogenes Amaral Silva
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Contributions

Conception and design of the study (VDAS, DF, TFO, YNF, FHAL, MCSJ, JSA); acquisition of data (CCS, TRCP, LS, LAFF, PM, AMANA, ACSC, JTS, EOR, FLP, DBB, MRB), analysis and interpretation of data (VDAS, SLC, MFDC, DF, TFO, YNF, FHAL, MCSJ, SSRP); drafting the article or revising it critically for important intellectual content (VDAS, SLC, MFDC, DF, TFO, YNF, FHAL, MCSJ, SSRP, JSA).

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Correspondence to Victor Diogenes Amaral Silva.

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Santos, C.C., Cardim-Pires, T.R., Shvachiy, L. et al. JM-20, a Benzodiazepine-Dihydropyridine Hybrid Molecule, Inhibits the Formation of Alpha-Synuclein-Aggregated Species. Neurotox Res 40, 2135–2147 (2022). https://doi.org/10.1007/s12640-022-00559-7

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