Neuroprotective Action of Multitarget 7-Aminophenanthridin-6(5H)-one Derivatives against Metal-Induced Cell Death and Oxidative Stress in SN56 Cells

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Moyano-Cires Ivanoff, Paula Viviana and Vicente Zurdo, David and Blázquez-Barbadillo, Cristina and Menéndez Ramos, José Carlos and González Matilla, Juan Francisco and Rosales Conrado, Noelia and Pino Sans, Javier del (2021) Neuroprotective Action of Multitarget 7-Aminophenanthridin-6(5H)-one Derivatives against Metal-Induced Cell Death and Oxidative Stress in SN56 Cells. ACS Chemical Neuroscience, 12 (18). pp. 3358-3372. ISSN 1948-7193

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Official URL: https://doi.org/10.1021/acschemneuro.1c00333




Abstract

Neurodegenerative diseases have been associated with brain metal accumulation, which produces oxidative stress (OS), matrix metalloproteinases (MMPs) induction, and neuronal cell death. Several metals have been reported to downregulate both the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and the antioxidant enzymes regulated by it, mediating OS induction and neurodegeneration. Among a recently discovered family of multitarget 7-amino-phenanthridin-6-one derivatives (APH) the most promising compounds were tested against metal-induced cell death and OS in SN56 cells. These compounds, designed to have chelating activity, are known to inhibit some MMPs and to present antioxidant and neuroprotective effects against hydrogen peroxide treatment to SN56 neuronal cells. However, the mechanisms that mediate this protective effect are not fully understood. The obtained results show that compounds APH1, APH2, APH3, APH4, and APH5 were only able to chelate iron and copper ions among all metals studied and that APH3, APH4, and APH5 were also able to chelate mercury ion. However, none of them was able to chelate zinc, cadmium, and aluminum, thus exhibiting selective chelating activity that can be partly responsible for their neuroprotective action. Otherwise, our results indicate that their antioxidant effect is mediated through induction of the Nrf2 pathway that leads to overexpression of antioxidant enzymes. Finally, these compounds exhibited neuroprotective effects, reversing partially or completely the cytotoxic effects induced by the metals studied depending on the compound used. APH4 was the most effective and safe compound.


Item Type:Article
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CRUE-CSIC (Acuerdos Transformativos 2021)

Uncontrolled Keywords:Metal cytotoxicity, neuroprotection, chelating activity, antioxidants, phenanthridones
Subjects:Sciences > Chemistry > Chemical engineering
Sciences > Chemistry > Analytic chemistry
Medical sciences > Pharmacy > Pharmacology
Medical sciences > Pharmacy > Inorganic chemistry
ID Code:69341
Deposited On:21 Dec 2021 11:03
Last Modified:18 Feb 2022 11:02

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