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

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.

• Authors: Cleonice Creusa Santos, Thyago R Cardim-Pires, Liana Shvachiy, Luis Arturo Fonseca-Fonseca, Patricia Muñoz, Áurea Maria A N Almeida, Ana Carla S Costa, Jéssica Teles-Souza, Estael Ochoa-Rodríguez, Maria de Fátima Dias Costa, Fernando L Palhano, Juan Segura-Aguilar, Deyse B Barbosa, Mayra R do Bomfim, Manoelito C Dos Santos Junior, Franco Henrique A Leite, Samuel Silva da Rocha Pita, Silvia Lima Costa, Yanier Núñez-Figueredo, Tiago Fleming Outeiro, Débora Foguel, Victor Diogenes Amaral Silva
• Journal: Neurotoxicity research (Neurotox Res) Vol. 40 Issue 6 Pg. 2135-2147 (Dec 2022) ISSN: 1476-3524 [Electronic] United States
• PMID: 35997936 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• alpha-Synuclein
• aminochrome 1
• Benzodiazepines
• Dihydropyridines

Topics

• Humans
• alpha-Synuclein
• Benzodiazepines
• Molecular Docking Simulation
• Neuroblastoma
• Parkinson Disease (drug therapy)
• Dihydropyridines