Abstract
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that binds to the antioxidant response element, a cis-acting regulatory element that increases expression of detoxifying enzymes and antioxidant proteins. Kelch-like ECH associating protein 1 (Keap1) protein is a negative regulator of Nrf2. Previous work has shown that genetic overexpression of Nrf2 is protective in vitro and in vivo. To modulate the Nrf2-ARE system without overexpressing Nrf2, we used short interfering RNA (siRNA) directed against Keap1. Keap1 siRNA administration in primary astrocytes increased the levels of Nrf2-ARE driven genes and protected against oxidative stress. Moreover, Keap1 siRNA resulted in a persistent upregulation of the Nrf2-ARE pathway and protection against oxidative stress in primary astrocytes. Keap1 siRNA injected into the striatum was also modestly protective against MPTP-induced dopaminergic terminal damage. These data indicate that activation of endogenous intracellular levels of Nrf2 is sufficient to protect in models of oxidative stress and Parkinson's disease.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism
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Antioxidants / metabolism*
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Astrocytes / drug effects*
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Astrocytes / metabolism
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Astrocytes / pathology
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Binding Sites
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Biomarkers, Tumor / genetics
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Biomarkers, Tumor / metabolism
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Cells, Cultured
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Cytoprotection
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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Disease Models, Animal
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Dopaminergic Neurons / drug effects
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Dopaminergic Neurons / metabolism
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Dopaminergic Neurons / pathology
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Dose-Response Relationship, Drug
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Genetic Therapy / methods*
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Kelch-Like ECH-Associated Protein 1
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Lectins, C-Type / genetics
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Lectins, C-Type / metabolism
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MPTP Poisoning / genetics
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MPTP Poisoning / metabolism
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MPTP Poisoning / pathology
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MPTP Poisoning / prevention & control*
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Mice
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Mice, Transgenic
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NF-E2-Related Factor 2 / metabolism*
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Oxidants / toxicity
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Oxidative Stress / drug effects*
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Pancreatitis-Associated Proteins
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RNA Interference*
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RNA, Small Interfering / metabolism*
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Response Elements*
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Time Factors
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Transfection
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tert-Butylhydroperoxide / toxicity
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Neoplasm
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Antioxidants
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Biomarkers, Tumor
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Cytoskeletal Proteins
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Keap1 protein, mouse
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Kelch-Like ECH-Associated Protein 1
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Lectins, C-Type
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NF-E2-Related Factor 2
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Nfe2l2 protein, mouse
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Oxidants
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Pancreatitis-Associated Proteins
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RNA, Small Interfering
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tert-Butylhydroperoxide