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Different Susceptibility to the Parkinson's Toxin MPTP in Mice Lacking the Redox Master Regulator Nrf2 or Its Target Gene Heme Oxygenase-1
BACKGROUND: The transcription factor Nrf2 (NF-E2-related factor 2) and its target gene products, including heme oxygenase-1 (HO-1), elicit an antioxidant response that may have therapeutic value for Parkinson's disease (PD). However, HO-1 protein levels are increased in dopaminergic neurons of...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911386/ https://www.ncbi.nlm.nih.gov/pubmed/20676377 http://dx.doi.org/10.1371/journal.pone.0011838 |
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author | Innamorato, Nadia G. Jazwa, Agnieszka Rojo, Ana I. García, Concepción Fernández-Ruiz, Javier Grochot–Przeczek, Anna Stachurska, Anna Jozkowicz, Alicja Dulak, Jozef Cuadrado, Antonio |
author_facet | Innamorato, Nadia G. Jazwa, Agnieszka Rojo, Ana I. García, Concepción Fernández-Ruiz, Javier Grochot–Przeczek, Anna Stachurska, Anna Jozkowicz, Alicja Dulak, Jozef Cuadrado, Antonio |
author_sort | Innamorato, Nadia G. |
collection | PubMed |
description | BACKGROUND: The transcription factor Nrf2 (NF-E2-related factor 2) and its target gene products, including heme oxygenase-1 (HO-1), elicit an antioxidant response that may have therapeutic value for Parkinson's disease (PD). However, HO-1 protein levels are increased in dopaminergic neurons of Parkinson's disease (PD) patients, suggesting its participation in free-iron deposition, oxidative stress and neurotoxicity. Before targeting Nrf2 for PD therapy it is imperative to determine if HO-1 is neurotoxic or neuroprotective in the basal ganglia. METHODOLOGY: We addressed this question by comparing neuronal damage and gliosis in Nrf2- or HO-1-knockout mice submitted to intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for five consecutive days. Nrf2-knockout mice showed exacerbated gliosis and dopaminergic nigrostriatal degeneration, as determined by immunohistochemical staining of tyrosine hydroxylase in striatum (STR) and substantia nigra (SN) and by HPLC determination of striatal dopamine and 3,4- dihydroxyphenylacetic acid (DOPAC). On the other hand, the severity of gliosis and dopaminergic degeneration in HO-1-null mice was neither increased nor reduced. Regarding free-iron deposition, both Nrf2- and HO-1-deficient mice exhibited similar number of deposits as determined by Perl's staining, therefore indicating that these proteins do not contribute significantly to iron accumulation or clearance in MPTP-induced Parkinsonism. CONCLUSIONS: These results suggest that HO-1 does not protect or enhance the sensitivity to neuronal death in Parkinson's disease and that pharmacological or genetic intervention on Nrf2 may provide a neuroprotective benefit as add on therapy with current symptomatic protocols. |
format | Text |
id | pubmed-2911386 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29113862010-07-30 Different Susceptibility to the Parkinson's Toxin MPTP in Mice Lacking the Redox Master Regulator Nrf2 or Its Target Gene Heme Oxygenase-1 Innamorato, Nadia G. Jazwa, Agnieszka Rojo, Ana I. García, Concepción Fernández-Ruiz, Javier Grochot–Przeczek, Anna Stachurska, Anna Jozkowicz, Alicja Dulak, Jozef Cuadrado, Antonio PLoS One Research Article BACKGROUND: The transcription factor Nrf2 (NF-E2-related factor 2) and its target gene products, including heme oxygenase-1 (HO-1), elicit an antioxidant response that may have therapeutic value for Parkinson's disease (PD). However, HO-1 protein levels are increased in dopaminergic neurons of Parkinson's disease (PD) patients, suggesting its participation in free-iron deposition, oxidative stress and neurotoxicity. Before targeting Nrf2 for PD therapy it is imperative to determine if HO-1 is neurotoxic or neuroprotective in the basal ganglia. METHODOLOGY: We addressed this question by comparing neuronal damage and gliosis in Nrf2- or HO-1-knockout mice submitted to intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for five consecutive days. Nrf2-knockout mice showed exacerbated gliosis and dopaminergic nigrostriatal degeneration, as determined by immunohistochemical staining of tyrosine hydroxylase in striatum (STR) and substantia nigra (SN) and by HPLC determination of striatal dopamine and 3,4- dihydroxyphenylacetic acid (DOPAC). On the other hand, the severity of gliosis and dopaminergic degeneration in HO-1-null mice was neither increased nor reduced. Regarding free-iron deposition, both Nrf2- and HO-1-deficient mice exhibited similar number of deposits as determined by Perl's staining, therefore indicating that these proteins do not contribute significantly to iron accumulation or clearance in MPTP-induced Parkinsonism. CONCLUSIONS: These results suggest that HO-1 does not protect or enhance the sensitivity to neuronal death in Parkinson's disease and that pharmacological or genetic intervention on Nrf2 may provide a neuroprotective benefit as add on therapy with current symptomatic protocols. Public Library of Science 2010-07-28 /pmc/articles/PMC2911386/ /pubmed/20676377 http://dx.doi.org/10.1371/journal.pone.0011838 Text en Innamorato et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Innamorato, Nadia G. Jazwa, Agnieszka Rojo, Ana I. García, Concepción Fernández-Ruiz, Javier Grochot–Przeczek, Anna Stachurska, Anna Jozkowicz, Alicja Dulak, Jozef Cuadrado, Antonio Different Susceptibility to the Parkinson's Toxin MPTP in Mice Lacking the Redox Master Regulator Nrf2 or Its Target Gene Heme Oxygenase-1 |
title | Different Susceptibility to the Parkinson's Toxin MPTP in Mice Lacking the Redox Master Regulator Nrf2 or Its Target Gene Heme Oxygenase-1 |
title_full | Different Susceptibility to the Parkinson's Toxin MPTP in Mice Lacking the Redox Master Regulator Nrf2 or Its Target Gene Heme Oxygenase-1 |
title_fullStr | Different Susceptibility to the Parkinson's Toxin MPTP in Mice Lacking the Redox Master Regulator Nrf2 or Its Target Gene Heme Oxygenase-1 |
title_full_unstemmed | Different Susceptibility to the Parkinson's Toxin MPTP in Mice Lacking the Redox Master Regulator Nrf2 or Its Target Gene Heme Oxygenase-1 |
title_short | Different Susceptibility to the Parkinson's Toxin MPTP in Mice Lacking the Redox Master Regulator Nrf2 or Its Target Gene Heme Oxygenase-1 |
title_sort | different susceptibility to the parkinson's toxin mptp in mice lacking the redox master regulator nrf2 or its target gene heme oxygenase-1 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2911386/ https://www.ncbi.nlm.nih.gov/pubmed/20676377 http://dx.doi.org/10.1371/journal.pone.0011838 |
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