Development of an iron-selective antioxidant probe with protective effects on neuronal function

Olimpo Garćia-Beltran, Natalia P. Mena, Pabla Aguirre, German Barriga-Gonzalez, Antonio Galdamez, Edgar Nagles, Tatiana Adasme, Cecilia Hidalgo, Marco T. Nuñez

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Iron accumulation, oxidative stress and calcium signaling dysregulation are common pathognomonic signs of several neurodegenerative diseases, including Parkinsońs and Alzheimer's diseases, Friedreich ataxia and Huntington's disease. Given their therapeutic potential, the identification of multifunctional compounds that suppress these damaging features is highly desirable. Here, we report the synthesis and characterization of N-(1, 3-dihy-droxy-2-(hydroxymethyl) propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl) acetamide, named CT51, which exhibited potent free radical neutralizing activity both in vitroand in cells. CT51 bound Fe2+ with high selectivity and Fe3+ with somewhat lower affinity. Cyclic voltammetric analysis revealed irreversible binding of Fe3+ to CT51, an important finding since stopping Fe2+/Fe3+ cycling in cells should prevent hydroxyl radical production resulting from the Fenton-Haber-Weiss cycle. When added to human neuroblastoma cells, CT51 freely permeated the cell membrane and distributed to both mitochondria and cytoplasm. Intracellularly, CT51 bound iron reversibly and protected against lipid peroxidation. Treatment of primary hippocampal neurons with CT51 reduced the sustained calcium release induced by an agonist of ryanodine receptor-calcium channels. These protective properties of CT51 on cellular function highlight its possible therapeutic use in diseases with significant oxidative, iron and calcium dysregulation.

Original languageEnglish
Article numbere0189043
JournalPLoS ONE
Volume12
Issue number12
DOIs
StatePublished - Dec 2017

Bibliographical note

Funding Information:
Funding:Thisstudywassupportedbythe Comisio ´n Nacional de Investigacio ´n Cientı ´fica y Tecnolo ´gica(CONICYT),Chile(http://spl.conicyt.cl/ auth/),whichprovidedapostdoctoralresearch grant (N˚ 3149451) to Dr. Olimpo Garcı ´ a-Beltra ´ n; Fondo Nacional de Desarrollo Cientı ´ fico y Tecnolo ´ gica(FONDECYT),Chile(http://www.

Publisher Copyright:
© 2017 Garćia-Beltrán et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

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