Moyano, PaulaVicente-Zurdo, DavidBlázquez-Barbadillo, CristinaMenéndez, J. CarlosGonzález, Juan FRosales-Conrado, Noeliadel Pino, Javier2024-10-222024-10-222022-09Moyano P, Vicente-Zurdo D, Blázquez-Barbadillo C, Menéndez JC, González JF, Rosales-Conrado N, Pino JD. Neuroprotective mechanisms of multitarget 7-aminophenanthridin-6(5H)-one derivatives against metal-induced amyloid proteins generation and aggregation. Food Chem Toxicol. 2022 Sep;167:113264. doi: 10.1016/j.fct.2022.113264. Epub 2022 Jun 30. PMID: 35781037.0278-6915 (print)1873-6351 (online)https://hdl.handle.net/10115/40504Brain'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 proteinsengAttribution-NonCommercial-NoDerivatives 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Amyloid proteinsHSP70Metal neurotoxicityPhenanthridonesProteasome 20SSN56 basal forebrain cholinergic neuronsinfo:eu-repo/semantics/article10.1016/j.fct.2022.113264info:eu-repo/semantics/openAccess