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PMID: 14762128 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

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.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 24 ·No. 5 ·2004-02-04 ·Pages 1101-12

Kraft AD, Johnson DA, Johnson JA

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.

MeSH Terms
Adenoviridae/genetics Animals Antioxidants/pharmacology Astrocytes/cytology,drug effects,metabolism Calcium-Transporting ATPases/antagonists & inhibitors Cell Death/drug effects Cell Separation Cells, Cultured Cytoprotection/drug effects,physiology DNA-Binding Proteins/biosynthesis,genetics Enzyme Inhibitors/pharmacology Glutamic Acid/toxicity Humans Hydroquinones/pharmacology Isothiocyanates Mice Mice, Transgenic NF-E2-Related Factor 2 Neurons/cytology,drug effects,metabolism Neuroprotective Agents/pharmacology Oxidants/toxicity Oxidative Stress/drug effects,physiology Phosphoinositide-3 Kinase Inhibitors Response Elements/drug effects,physiology Sulfoxides Thiocyanates/pharmacology Trans-Activators/biosynthesis,genetics
Chemicals
Antioxidants DNA-Binding Proteins Enzyme Inhibitors Hydroquinones Isothiocyanates NF-E2-Related Factor 2 NFE2L2 protein, human Neuroprotective Agents Nfe2l2 protein, mouse Oxidants Phosphoinositide-3 Kinase Inhibitors Sulfoxides Thiocyanates Trans-Activators Glutamic Acid 2-tert-butylhydroquinone Calcium-Transporting ATPases sulforaphane
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Kraft Andrew D
School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705-2222, USA.
Johnson Delinda A
Johnson Jeffrey A
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.3817-03.2004
Published
2004-02-04
Pages
1101-12
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6793572
Subset
IM
Grants
NIEHS NIH HHS · R01 ES008089 · United States
NIEHS NIH HHS · R29 ES008089 · United States
NIEHS NIH HHS · R01 ES010042 · United States
NIEHS NIH HHS · ES10042 · United States
NIEHS NIH HHS · ES08089 · United States
NIEHS NIH HHS · ES09090 · United States
External Links
PubMed source DOI: 10.1523/JNEUROSCI.3817-03.2004 PMC Full Text View journal details
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