Neuroprotective mechanisms of multitarget 7-aminophenanthridin-6(5H)-one derivatives against metal-induced amyloid proteins generation and aggregation

• Published in: Food and chemical toxicology 2022-09, Vol.167, p.113264-113264, Article 113264
• Main Authors: Moyano, Paula, Vicente-Zurdo, David, Blázquez-Barbadillo, Cristina, Menéndez, J. Carlos, González, Juan F., Rosales-Conrado, Noelia, Pino, Javier del
• Format: Article
• Language: English
• Subjects: amyloid; Amyloid proteins; antioxidant activity; brain; cadmium; cell death; heat stress; HSP70; iron; Metal neurotoxicity; neurodegenerative diseases; neurons; neurotoxicity; Phenanthridones; Proteasome 20S; proteasome endopeptidase complex; SN56 basal forebrain cholinergic neurons; therapeutics; toxicology
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2022.113264

Brain's metals accumulation is associated with toxic proteins, like amyloid-proteins (Aβ), 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 Aβ proteins aggregation; the APH1-5 effect on HSP70 and proteasome 20S (P20S) expression, the metals effect on Aβ formation and the involvement of HSP70 and P20S in the process, and the APH1-5 neuroprotective effects against Aβ proteins (1 μM) and metals in SN56 cells. Our results show that APH1-5 compounds chemically avoid metal-induced Aβ proteins aggregation and induce HSP70 and P20S expression. Additionally, iron and cadmium induced Aβ proteins formation through downregulation of HSP70 and P20S. Finally, APH1-5 compounds protected against Aβ 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. [Display omitted] •APH1-5 compounds chemically avoid metal-induced Aβ proteins aggregation.•APH1-5 compounds induce HSP70 and P20S expression in SN56 cholinergic cells.•Iron and cadmium induced Aβ proteins formation through downregulation of HSP70 and P20S.•APH1-5 compounds protected against Aβ proteins-induced neuronal cell death.