Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism

Current therapies for motor symptoms of Parkinson's disease (PD) are based on dopamine replacement. However, the disease progression remains unaffected, because of continuous dopaminergic neuron loss. Since oxidative stress is actively involved in neuronal death in PD, pharmacological targeting...

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Autores: Jazwa, Agnieszka, Rojo, Ana I., Innamorato, Nadia G., Hesse, Marlen, Fernández-Ruiz, Javier, Cuadrado, Antonio
Tipo de recurso: artículo
Fecha de publicación:2011
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/40180
Acceso en línea:http://hdl.handle.net/10261/40180
Access Level:acceso abierto
Palabra clave:Oxidative stress
Sulforaphane
Mice
Neuroinflammation
Astrocytes
Pathway
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spelling Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonismJazwa, AgnieszkaRojo, Ana I.Innamorato, Nadia G.Hesse, MarlenFernández-Ruiz, JavierCuadrado, AntonioOxidative stressSulforaphaneMiceNeuroinflammationAstrocytesPathwayCurrent therapies for motor symptoms of Parkinson's disease (PD) are based on dopamine replacement. However, the disease progression remains unaffected, because of continuous dopaminergic neuron loss. Since oxidative stress is actively involved in neuronal death in PD, pharmacological targeting of the antioxidant machinery may have therapeutic value. Here, we analyzed the relevance of the antioxidant phase II response mediated by the transcription factor NF-E2-related factor 2 (Nrf2) on brain protection against the parkinsonian toxin methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Intraperitoneal administration of the potent Nrf2 activator sulforaphane (SFN) increased Nrf2 protein levels in the basal ganglia and led to upregulation of phase II antioxidant enzymes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase (NQO1). In wild-type mice, but not in Nrf2-knockout mice, SFN protected against MPTP-induced death of nigral dopaminergic neurons. The neuroprotective effects were accompanied by a decrease in astrogliosis, microgliosis, and release of pro-inflammatory cytokines. These results provide strong pharmacokinetic and biochemical evidence for activation of Nrf2 and phase II genes in the brain and also offer a neuroprotective strategy that may have clinical relevance for PD therapy.This work was supported by a Target Validation Grant of the Michael J. Fox Foundation for Parkinson’s Research and grant SAF2010-17822 from the Spanish Ministery of Science and Innovation. N.G.I. is recipient of a fellowship FPU from Universidad Autónoma of Madrid.Peer reviewedMary Ann Liebert201120112011info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501http://hdl.handle.net/10261/40180reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1089/ars.2010.3731info:eu-repo/semantics/openAccessoai:digital.csic.es:10261/401802026-05-22T06:33:51Z
dc.title.none.fl_str_mv Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism
title Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism
spellingShingle Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism
Jazwa, Agnieszka
Oxidative stress
Sulforaphane
Mice
Neuroinflammation
Astrocytes
Pathway
title_short Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism
title_full Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism
title_fullStr Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism
title_full_unstemmed Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism
title_sort Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism
dc.creator.none.fl_str_mv Jazwa, Agnieszka
Rojo, Ana I.
Innamorato, Nadia G.
Hesse, Marlen
Fernández-Ruiz, Javier
Cuadrado, Antonio
author Jazwa, Agnieszka
author_facet Jazwa, Agnieszka
Rojo, Ana I.
Innamorato, Nadia G.
Hesse, Marlen
Fernández-Ruiz, Javier
Cuadrado, Antonio
author_role author
author2 Rojo, Ana I.
Innamorato, Nadia G.
Hesse, Marlen
Fernández-Ruiz, Javier
Cuadrado, Antonio
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Oxidative stress
Sulforaphane
Mice
Neuroinflammation
Astrocytes
Pathway
topic Oxidative stress
Sulforaphane
Mice
Neuroinflammation
Astrocytes
Pathway
description Current therapies for motor symptoms of Parkinson's disease (PD) are based on dopamine replacement. However, the disease progression remains unaffected, because of continuous dopaminergic neuron loss. Since oxidative stress is actively involved in neuronal death in PD, pharmacological targeting of the antioxidant machinery may have therapeutic value. Here, we analyzed the relevance of the antioxidant phase II response mediated by the transcription factor NF-E2-related factor 2 (Nrf2) on brain protection against the parkinsonian toxin methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Intraperitoneal administration of the potent Nrf2 activator sulforaphane (SFN) increased Nrf2 protein levels in the basal ganglia and led to upregulation of phase II antioxidant enzymes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase (NQO1). In wild-type mice, but not in Nrf2-knockout mice, SFN protected against MPTP-induced death of nigral dopaminergic neurons. The neuroprotective effects were accompanied by a decrease in astrogliosis, microgliosis, and release of pro-inflammatory cytokines. These results provide strong pharmacokinetic and biochemical evidence for activation of Nrf2 and phase II genes in the brain and also offer a neuroprotective strategy that may have clinical relevance for PD therapy.
publishDate 2011
dc.date.none.fl_str_mv 2011
2011
2011
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/40180
url http://hdl.handle.net/10261/40180
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1089/ars.2010.3731
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Mary Ann Liebert
publisher.none.fl_str_mv Mary Ann Liebert
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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