Neuroprotective mechanisms of multitarget 7-aminophenanthridin-6(5H)-one derivatives against metal-induced amyloid proteins generation and aggregation. (September 2022)

• Record Type: Journal Article
• Authors: Moyano, Paula; Vicente-Zurdo, David; Blázquez-Barbadillo, Cristina; Menéndez, J. Carlos; González, Juan F.; Rosales-Conrado, Noelia; Pino, Javier del
• Is Part Of: Food and chemical toxicology. Volume 167(2022)
• Publication Date: 2022-09
• Subjects: Phenanthridones -- SN56 basal forebrain cholinergic neurons -- Metal neurotoxicity -- HSP70 -- Proteasome 20S -- Amyloid proteins; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2022.113264
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: 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. Graphical abstract: Image 1 Highlights: 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.