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

Lookup NU author(s): Professor Tiago OuteiroORCiD

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Abstract

© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.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.

Publication metadata

Author(s): Santos CC, Cardim-Pires TR, Shvachiy L, Fonseca-Fonseca LA, Munoz P, Almeida AMAN, Costa ACS, Teles-Souza J, Ochoa-Rodriguez E, de Fatima Dias Costa M, Palhano FL, Segura-Aguilar J, Barbosa DB, do Bomfim MR, dos Santos Junior MC, Leite FHA, da Rocha Pita SS, Costa SL, Nunez-Figueredo Y, Outeiro TF, Foguel D, Silva VDA

Publication type: Article

Publication status: Published

Journal: Neurotoxicity Research

Year: 2022

Volume: 40

Pages: 2135-2147

Print publication date: 01/12/2022

Online publication date: 23/08/2022

Acceptance date: 11/08/2022

ISSN (print): 1029-8428

ISSN (electronic): 1476-3524

Publisher: Springer

URL: https://doi.org/10.1007/s12640-022-00559-7

DOI: 10.1007/s12640-022-00559-7

PubMed id: 35997936

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