Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD involve oxidative stress and mitochondrial dysfunction. Administ...

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Autores principales:	Dirleise Colle, Danúbia Bonfanti Santos, Eduardo Luiz Gasnhar Moreira, Juliana Montagna Hartwig, Alessandra Antunes dos Santos, Luciana Teixeira Zimmermann, Mariana Appel Hort, Marcelo Farina
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/49decc64f14c41a2a0e79c6215755cf7
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spelling	oai:doaj.org-article:49decc64f14c41a2a0e79c6215755cf72021-11-18T07:41:35ZProbucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.1932-620310.1371/journal.pone.0067658https://doaj.org/article/49decc64f14c41a2a0e79c6215755cf72013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23799154/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD involve oxidative stress and mitochondrial dysfunction. Administration of 3-nitropropionic acid (3-NP), an irreversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, in rodents has been proposed as a useful experimental model of HD. This study evaluated the effects of probucol, a lipid-lowering agent with anti-inflammatory and antioxidant properties, on the biochemical parameters related to oxidative stress, as well as on the behavioral parameters related to motor function in an in vivo HD model based on 3-NP intoxication in rats. Animals were treated with 3.5 mg/kg of probucol in drinking water daily for 2 months and, subsequently, received 3-NP (25 mg/kg i.p.) once a day for 6 days. At the end of the treatments, 3-NP-treated animals showed a significant decrease in body weight, which corresponded with impairment on motor ability, inhibition of mitochondrial complex II activity and oxidative stress in the striatum. Probucol, which did not rescue complex II inhibition, protected against behavioral and striatal biochemical changes induced by 3-NP, attenuating 3-NP-induced motor impairments and striatal oxidative stress. Importantly, probucol was able to increase activity of glutathione peroxidase (GPx), an enzyme important in mediating the detoxification of peroxides in the central nervous system. The major finding of this study was that probucol protected against 3-NP-induced behavioral and striatal biochemical changes without affecting 3-NP-induced mitochondrial complex II inhibition, indicating that long-term probucol treatment resulted in an increased resistance against neurotoxic events (i.e., increased oxidative damage) secondary to mitochondrial dysfunction. These data appeared to be of great relevance when extrapolated to human neurodegenerative processes involving mitochondrial dysfunction and indicates that GPx is an important molecular target involved in the beneficial effects of probucol.Dirleise ColleDanúbia Bonfanti SantosEduardo Luiz Gasnhar MoreiraJuliana Montagna HartwigAlessandra Antunes dos SantosLuciana Teixeira ZimmermannMariana Appel HortMarcelo FarinaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 6, p e67658 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Dirleise Colle Danúbia Bonfanti Santos Eduardo Luiz Gasnhar Moreira Juliana Montagna Hartwig Alessandra Antunes dos Santos Luciana Teixeira Zimmermann Mariana Appel Hort Marcelo Farina Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.
description	Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease characterized by symptoms attributable to the death of striatal and cortical neurons. The molecular mechanisms mediating neuronal death in HD involve oxidative stress and mitochondrial dysfunction. Administration of 3-nitropropionic acid (3-NP), an irreversible inhibitor of the mitochondrial enzyme succinate dehydrogenase, in rodents has been proposed as a useful experimental model of HD. This study evaluated the effects of probucol, a lipid-lowering agent with anti-inflammatory and antioxidant properties, on the biochemical parameters related to oxidative stress, as well as on the behavioral parameters related to motor function in an in vivo HD model based on 3-NP intoxication in rats. Animals were treated with 3.5 mg/kg of probucol in drinking water daily for 2 months and, subsequently, received 3-NP (25 mg/kg i.p.) once a day for 6 days. At the end of the treatments, 3-NP-treated animals showed a significant decrease in body weight, which corresponded with impairment on motor ability, inhibition of mitochondrial complex II activity and oxidative stress in the striatum. Probucol, which did not rescue complex II inhibition, protected against behavioral and striatal biochemical changes induced by 3-NP, attenuating 3-NP-induced motor impairments and striatal oxidative stress. Importantly, probucol was able to increase activity of glutathione peroxidase (GPx), an enzyme important in mediating the detoxification of peroxides in the central nervous system. The major finding of this study was that probucol protected against 3-NP-induced behavioral and striatal biochemical changes without affecting 3-NP-induced mitochondrial complex II inhibition, indicating that long-term probucol treatment resulted in an increased resistance against neurotoxic events (i.e., increased oxidative damage) secondary to mitochondrial dysfunction. These data appeared to be of great relevance when extrapolated to human neurodegenerative processes involving mitochondrial dysfunction and indicates that GPx is an important molecular target involved in the beneficial effects of probucol.
format	article
author	Dirleise Colle Danúbia Bonfanti Santos Eduardo Luiz Gasnhar Moreira Juliana Montagna Hartwig Alessandra Antunes dos Santos Luciana Teixeira Zimmermann Mariana Appel Hort Marcelo Farina
author_facet	Dirleise Colle Danúbia Bonfanti Santos Eduardo Luiz Gasnhar Moreira Juliana Montagna Hartwig Alessandra Antunes dos Santos Luciana Teixeira Zimmermann Mariana Appel Hort Marcelo Farina
author_sort	Dirleise Colle
title	Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.
title_short	Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.
title_full	Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.
title_fullStr	Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.
title_full_unstemmed	Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.
title_sort	probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/49decc64f14c41a2a0e79c6215755cf7
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Probucol increases striatal glutathione peroxidase activity and protects against 3-nitropropionic acid-induced pro-oxidative damage in rats.

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