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

• Published in: Neurotoxicity research Vol. 40; no. 6; pp. 2135 - 2147
• Main Authors: Santos, Cleonice Creusa, Cardim-Pires, Thyago R., Shvachiy, Liana, Fonseca-Fonseca, Luis Arturo, Muñoz, Patricia, Almeida, Áurea Maria A. N., Costa, Ana Carla S., Teles-Souza, Jéssica, Ochoa-Rodríguez, Estael, de Fátima Dias Costa, Maria, Palhano, Fernando L., Segura-Aguilar, Juan, Barbosa, Deyse B., do Bomfim, Mayra R., dos Santos Junior, Manoelito C., Leite, Franco Henrique A., da Rocha Pita, Samuel Silva, Costa, Silvia Lima, Núñez-Figueredo, Yanier, Outeiro, Tiago Fleming, Foguel, Débora, Silva, Victor Diogenes Amaral
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2022
• Subjects: alpha-Synuclein; Benzodiazepines; Biomedical and Life Sciences; Biomedicine; Cell Biology; Dihydropyridines; Humans; Molecular Docking Simulation; Neurobiology; Neuroblastoma; Neurochemistry; Neurology; Neurosciences; Parkinson Disease - drug therapy; Pharmacology/Toxicology; Research Article; Neuroprotection; Neurotoxicity; Parkinson’s disease; Alpha-synuclein; JM-20
• ISSN: 1029-8428; 1476-3524
• DOI: 10.1007/s12640-022-00559-7

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.