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      Nuclear Factor E2-Related Factor 2-Dependent Antioxidant Response Element Activation by tert-Butylhydroquinone and Sulforaphane Occurring Preferentially in Astrocytes Conditions Neurons against Oxidative Insult

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          Abstract

          Binding of the transcription factor nuclear factor E2-related factor 2 (Nrf2) to the antioxidant response element (ARE) in neural cells results in the induction of a battery of genes that can coordinate a protective response against a variety of oxidative stressors. In this study, tert-butylhydroquinone (tBHQ) and sulforaphane were used as activators of this pathway. Consistent with previous studies, treatment of primary cortical cultures from ARE reporter mice revealed selective promoter activity in astrocytes. This activation protected neurons from hydrogen peroxide and nonexcitotoxic glutamate toxicity. tBHQ treatment of cultures from Nrf2 knock-out animals resulted in neither ARE activation nor neuroprotection. By reintroducing Nrf2 via infection with a replication-deficient adenovirus (ad), both the genetic response and neuroprotection were rescued. Conversely, infection with adenovirus encoding dominant-negative (DN) Nrf2 (ad-DN-Nrf2) or pretreatment with the selective phosphatidylinositol-3 kinase inhibitor LY294002 inhibited the tBHQ-mediated promoter response and corresponding neuroprotection. Interestingly, the adenoviral infection showed a high selectivity for astrocytes over neurons. In an attempt to reveal some of the cell type-specific changes resulting from ARE activation, cultures were infected with adenovirus encoding green fluorescent protein (GFP) (ad-GFP) or ad-DN-Nrf2 (containing GFP) before tBHQ treatment. A glia-enriched population of GFP-infected cells was then isolated from a population of uninfected neurons using cell-sorting technology. Microarray analysis was used to evaluate potential glial versus neuron-specific contributions to the neuroprotective effects of ARE activation and Nrf2 dependence. Strikingly, the change in neuronal gene expression after tBHQ treatment was dependent on Nrf2 activity in the astrocytes. This suggests that Nrf2-dependent genetic changes alter neuron–glia interactions resulting in neuroprotection.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          4 February 2004
          : 24
          : 5
          : 1101-1112
          Affiliations
          [1 ]School of Pharmacy, [2 ]Waisman Center, and [3 ]Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin 53705
          Article
          PMC6793572 PMC6793572 6793572 0241101
          10.1523/JNEUROSCI.3817-03.2004
          6793572
          14762128
          b426a579-ef6b-49a4-ba5a-2654c960792c
          Copyright © 2004 Society for Neuroscience 0270-6474/04/241101-12.00/0
          History
          : 20 November 2003
          : 15 August 2003
          : 18 November 2003
          Categories
          Cellular/Molecular
          Custom metadata
          1101
          ARTICLE

          cell sorting,glia–neuron interaction,sulforaphane,microarray,Nrf2,neuroprotection,oxidative stress,antioxidant response element

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