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JM-20 protects against 6-hydroxydopamine-induced neurotoxicity in models of Parkinson's disease: Mitochondrial protection and antioxidant properties

Lookup NU author(s): Professor Tiago OuteiroORCiD

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Abstract

© 2020 Elsevier B.V. We have previously shown that JM-20, a new chemical entity consisting of 1,5-benzodiazepine fused to a dihydropyridine moiety, protects against rotenone-induced neurotoxicity in an experimental model of Parkinson's disease (PD). The aim of this study was to investigate the effect of a novel hybrid molecule, named JM-20, in in vitro and in vivo models of PD induced by 6-hydroxydopamine (6-OHDA). PC-12 cells were exposed to 6-OHDA and treated with JM-20. Protection against mitochondrial damage induced by 6-OHDA was also investigated using isolated rat brain mitochondria. We found that JM-20 protected PC-12 cells against cytotoxicity induced by 6-OHDA and inhibited hydrogen peroxide generation, mitochondrial swelling and membrane potential dissipation. For in vivo experiments, adult male Wistar rats were lesioned in the substantia nigra pars compacta (SNpc) by 6-OHDA administration. JM-20 was orally administered (10, 20 or 40 mg/kg), intragastric via gavage, 24 h after surgery and daily for seven days. Treatment with JM-20 significantly reduced the percentage of motor asymmetry and increased vertical exploration. It improved the redox state of the SNpc and the striatal tissue of these animals. Also, JM-20 reduced glial fibrillary acidic protein overexpression and increased tyrosine hydroxylase-positive cell number, both in SNpc. Altogether, these results demonstrate that JM-20 is a potential neuroprotective agent against 6-OHDA-induced damage in both in vitro and in vivo models. The mechanism underlying JM-20 neuroprotection against 6-OHDA appears to be associated with the control of oxidative injury and mitochondrial impairment.

Publication metadata

Author(s): Fonseca-Fonseca LA, da Silva VDA, Wong-Guerra M, Ramirez-Sanchez J, Yaquis ASP, Ochoa-Rodriguez E, Verdecia-Reyes Y, de Araujo FM, Santana RC, Outeiro TF, Costa SL, Nunez-Figueredo Y

Publication type: Article

Publication status: Published

Journal: NeuroToxicology

Year: 2021

Volume: 82

Pages: 89-98

Print publication date: 01/01/2021

Online publication date: 21/11/2020

Acceptance date: 16/11/2020

ISSN (print): 0161-813X

ISSN (electronic): 1872-9711

Publisher: Elsevier BV

URL: https://doi.org/10.1016/j.neuro.2020.11.005

DOI: 10.1016/j.neuro.2020.11.005

PubMed id: 33232743

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