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

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Moyano-Cires Ivanoff, Paula Viviana and Vicente Zurdo, David and Blázquez Barbadillo, Cristina and Menéndez, J. Carlos and González Matilla, Juan Francisco and Rosales Conrado, Noelia and Pino Sans, Javier del (2022) Neuroprotective mechanisms of multitarget 7-aminophenanthridin-6(5H)-one derivatives against metal-induced amyloid proteins generation and aggregation. Food and Chemical Toxicology, 167 . p. 113264. ISSN 0278-6915

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Official URL: https://doi.org/10.1016/j.fct.2022.113264



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.


Item Type:Article
Additional Information:

CRUE-CSIC (Acuerdos Transformativos 2022)

Uncontrolled Keywords:Phenanthridones, SN56 basal forebrain cholinergic neurons, Metal neurotoxicity, HSP70, Proteasome 20S, Amyloid proteins
Subjects:Medical sciences > Pharmacy > Pharmacology
Medical sciences > Pharmacy > Analytic chemistry
Medical sciences > Pharmacy > Toxicology
ID Code:73454
Deposited On:06 Jul 2022 08:57
Last Modified:06 Jul 2022 11:14

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