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Targeting NRF2 for the Treatment of Friedreich’s Ataxia: A Comparison among Drugs
NRF2 (Nuclear factor Erythroid 2-related Factor 2) signaling is impaired in Friedreich’s Ataxia (FRDA), an autosomal recessive disease characterized by progressive nervous system damage and degeneration of nerve fibers in the spinal cord and peripheral nerves. The loss of frataxin in patients result...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829337/ https://www.ncbi.nlm.nih.gov/pubmed/31640150 http://dx.doi.org/10.3390/ijms20205211 |
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author | Petrillo, Sara D’Amico, Jessica La Rosa, Piergiorgio Bertini, Enrico Silvio Piemonte, Fiorella |
author_facet | Petrillo, Sara D’Amico, Jessica La Rosa, Piergiorgio Bertini, Enrico Silvio Piemonte, Fiorella |
author_sort | Petrillo, Sara |
collection | PubMed |
description | NRF2 (Nuclear factor Erythroid 2-related Factor 2) signaling is impaired in Friedreich’s Ataxia (FRDA), an autosomal recessive disease characterized by progressive nervous system damage and degeneration of nerve fibers in the spinal cord and peripheral nerves. The loss of frataxin in patients results in iron sulfur cluster deficiency and iron accumulation in the mitochondria, making FRDA a fatal and debilitating condition. There are no currently approved therapies for the treatment of FRDA and molecules able to activate NRF2 have the potential to induce clinical benefits in patients. In this study, we compared the efficacy of six redox-active drugs, some already adopted in clinical trials, targeting NRF2 activation and frataxin expression in fibroblasts obtained from skin biopsies of FRDA patients. All of these drugs consistently increased NRF2 expression, but differential profiles of NRF2 downstream genes were activated. The Sulforaphane and N-acetylcysteine were particularly effective on genes involved in preventing inflammation and maintaining glutathione homeostasis, the dimethyl fumarate, omaxevolone, and EPI-743 in counteracting toxic products accumulation, the idebenone in mitochondrial protection. This study may contribute to develop synergic therapies, based on a combination of treatment molecules. |
format | Online Article Text |
id | pubmed-6829337 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-68293372019-11-18 Targeting NRF2 for the Treatment of Friedreich’s Ataxia: A Comparison among Drugs Petrillo, Sara D’Amico, Jessica La Rosa, Piergiorgio Bertini, Enrico Silvio Piemonte, Fiorella Int J Mol Sci Article NRF2 (Nuclear factor Erythroid 2-related Factor 2) signaling is impaired in Friedreich’s Ataxia (FRDA), an autosomal recessive disease characterized by progressive nervous system damage and degeneration of nerve fibers in the spinal cord and peripheral nerves. The loss of frataxin in patients results in iron sulfur cluster deficiency and iron accumulation in the mitochondria, making FRDA a fatal and debilitating condition. There are no currently approved therapies for the treatment of FRDA and molecules able to activate NRF2 have the potential to induce clinical benefits in patients. In this study, we compared the efficacy of six redox-active drugs, some already adopted in clinical trials, targeting NRF2 activation and frataxin expression in fibroblasts obtained from skin biopsies of FRDA patients. All of these drugs consistently increased NRF2 expression, but differential profiles of NRF2 downstream genes were activated. The Sulforaphane and N-acetylcysteine were particularly effective on genes involved in preventing inflammation and maintaining glutathione homeostasis, the dimethyl fumarate, omaxevolone, and EPI-743 in counteracting toxic products accumulation, the idebenone in mitochondrial protection. This study may contribute to develop synergic therapies, based on a combination of treatment molecules. MDPI 2019-10-21 /pmc/articles/PMC6829337/ /pubmed/31640150 http://dx.doi.org/10.3390/ijms20205211 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Petrillo, Sara D’Amico, Jessica La Rosa, Piergiorgio Bertini, Enrico Silvio Piemonte, Fiorella Targeting NRF2 for the Treatment of Friedreich’s Ataxia: A Comparison among Drugs |
title | Targeting NRF2 for the Treatment of Friedreich’s Ataxia: A Comparison among Drugs |
title_full | Targeting NRF2 for the Treatment of Friedreich’s Ataxia: A Comparison among Drugs |
title_fullStr | Targeting NRF2 for the Treatment of Friedreich’s Ataxia: A Comparison among Drugs |
title_full_unstemmed | Targeting NRF2 for the Treatment of Friedreich’s Ataxia: A Comparison among Drugs |
title_short | Targeting NRF2 for the Treatment of Friedreich’s Ataxia: A Comparison among Drugs |
title_sort | targeting nrf2 for the treatment of friedreich’s ataxia: a comparison among drugs |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829337/ https://www.ncbi.nlm.nih.gov/pubmed/31640150 http://dx.doi.org/10.3390/ijms20205211 |
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