Neuroprotective mechanisms of multitarget 7-aminophenanthridin-6(5H)-one derivatives against metal-induced amyloid proteins generation and aggregation.
Food Chem Toxicol
; 167: 113264, 2022 Sep.
Article
em En
| MEDLINE
| ID: mdl-35781037
ABSTRACT
Brain's metals accumulation is associated with toxic proteins, like amyloid-proteins (Aß), formation, accumulation, and aggregation, leading to neurodegeneration. Metals downregulate the correct folding, disaggregation, or degradation mechanisms of toxic proteins, as heat shock proteins (HSPs) and proteasome. The 7-amino-phenanthridin-6(5H)-one derivatives (APH) showed neuroprotective effects against metal-induced cell death through their antioxidant effect, independently of their chelating activity. However, additional neuroprotective mechanisms seem to be involved. We tested the most promising APH compounds (APH1-5, 10-100 µM) chemical ability to prevent metal-induced Aß proteins aggregation; the APH1-5 effect on HSP70 and proteasome 20S (P20S) expression, the metals effect on Aß formation and the involvement of HSP70 and P20S in the process, and the APH1-5 neuroprotective effects against Aß proteins (1 µM) and metals in SN56 cells. Our results show that APH1-5 compounds chemically avoid metal-induced Aß proteins aggregation and induce HSP70 and P20S expression. Additionally, iron and cadmium induced Aß proteins formation through downregulation of HSP70 and P20S. Finally, APH1-5 compounds protected against Aß proteins-induced neuronal cell death, reversing partially or completely this effect. These data may help to provide a new therapeutic approach against the neurotoxic effect induced by metals and other environmental pollutants, especially when mediated by toxic proteins.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fármacos Neuroprotetores
/
Doença de Alzheimer
Limite:
Humans
Idioma:
En
Revista:
Food Chem Toxicol
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Espanha