期刊
NEUROTOXICOLOGY
卷 82, 期 -, 页码 89-98出版社
ELSEVIER
DOI: 10.1016/j.neuro.2020.11.005
关键词
JM-20; Parkinson's disease; Neuroprotection; 6-Hydroxydopamine; Mitochondria; Oxidative stress
资金
- CAPES/MES (Brazil-Cuba) project [178/12 2]
- SCIENCE AND INNOVATION FINANCIAL FUND (FONCI-Cuba) [460020]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy [EXC 2067/1-390729940]
The novel compound JM-20 has shown neuroprotective effects against 6-OHDA-induced damage in both in vitro and in vivo models of Parkinson's disease. The mechanism of action involves controlling oxidative damage and mitochondrial dysfunction.
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 6OHDA 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.
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