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* Departamento de Bioquímica e Instituto de Investigaciones Biomédicas "Alberto Sols" Consejo Superior de Investigaciones Científicas-Universidad Autónoma, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain;
Centro de Investigación en Red en Enfermedades Neurodegenerativas, Madrid, Spain;
Center for Tsukuba Advanced Alliance and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan; and
Departamento de Neurobiología Celular, Molecular y del Desarrollo, Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain
Because chronic neuroinflammation is a hallmark of neurodegenerative diseases and compromises neuron viability, it is imperative to discover pharmacologic targets to modulate the activation of immune brain cells, the microglia. In this study, we identify the transcription factor Nrf2, guardian of redox homeostasis, as such target in a model of LPS-induced inflammation in mouse hippocampus. Nrf2 knockout mice were hypersensitive to the neuroinflammation induced by LPS, as determined by an increase in F4/80 mRNA and protein, indicative of an increase in microglial cells, and in the inflammation markers inducible NO synthase, IL-6, and TNF-
, compared with the hippocampi of wild-type littermates. The aliphatic isothiocyanate sulforaphane elicited an Nrf2-mediated antioxidant response in the BV2 microglial cell line, determined by flow cytometry of cells incubated with the redox sensitive probe dihydrodichlorofluorescein diacetate, and by the Nrf2-dependent induction of the phase II antioxidant enzyme heme oxygenase-1. Animals treated with sulforaphane displayed a 2–3-fold increase in heme oxygenase-1, a reduced abundance of microglial cells in the hippocampus and an attenuated production of inflammation markers (inducible NO synthase, IL-6, and TNF-) in response to LPS. Considering that release of reactive oxygen species is a property of activated microglia, we propose a model in which late induction of Nrf2 intervenes in the down-regulation of microglia. This study opens the possibility of targeting Nrf2 in brain as a means to modulate neuroinflammation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grants SAF2004-02039 and SAF2007-62646 from Ministerio de Educación y Ciencia of Spain and Grant 2004 of Fundación Mutua Madrileña Automovilística.
2 Address correspondence and reprint requests to Dr. Antonio Cuadrado, Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid, Arzobispo Morcillo 4, 28029 Madrid, Spain. E-mail address: antonio.cuadrado{at}uam.es
3 Abbreviations used in this paper: ROS, reactive oxygen species; ARE, antioxidant response element; H2DCFDA, dihydrodichlorofluorescein diacetate; HO-1, heme oxygenase-1; SFN, sulforaphane.
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  K. Kanninen, R. Heikkinen, T. Malm, T. Rolova, S. Kuhmonen, H. Leinonen, S. Yla-Herttuala, H. Tanila, A.-L. Levonen, M. Koistinaho, et al. Intrahippocampal injection of a lentiviral vector expressing Nrf2 improves spatial learning in a mouse model of Alzheimer's disease PNAS, September 22, 2009; 106(38): 16505 - 16510. [Abstract] [Full Text] [PDF]
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