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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2016

Open Access 01-12-2016 | Research

Pyrrolidine dithiocarbamate activates the Nrf2 pathway in astrocytes

Authors: Jeffrey R. Liddell, Sarka Lehtonen, Clare Duncan, Velta Keksa-Goldsteine, Anna-Liisa Levonen, Gundars Goldsteins, Tarja Malm, Anthony R. White, Jari Koistinaho, Katja M. Kanninen

Published in: Journal of Neuroinflammation | Issue 1/2016

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Abstract

Background

Endogenous defense against oxidative stress is controlled by nuclear factor erythroid 2-related factor 2 (Nrf2). The normal compensatory mechanisms to combat oxidative stress appear to be insufficient to protect against the prolonged exposure to reactive oxygen species during disease. Counterbalancing the effects of oxidative stress by up-regulation of Nrf2 signaling has been shown to be effective in various disease models where oxidative stress is implicated, including Alzheimer’s disease. Stimulation of Nrf2 signaling by small-molecule activators is an appealing strategy to up-regulate the endogenous defense mechanisms of cells.

Methods

Here, we investigate Nrf2 induction by the metal chelator and known nuclear factor-κB inhibitor pyrrolidine dithiocarbamate (PDTC) in cultured astrocytes and neurons, and mouse brain. Nrf2 induction is further examined in cultures co-treated with PDTC and kinase inhibitors or amyloid-beta, and in Nrf2-deficient cultures.

Results

We show that PDTC is a potent inducer of Nrf2 signaling specifically in astrocytes and demonstrate the critical role of Nrf2 in PDTC-mediated protection against oxidative stress. This induction appears to be regulated by both Keap1 and glycogen synthase kinase 3β. Furthermore, the presence of amyloid-beta magnifies PDTC-mediated induction of endogenous protective mechanisms, therefore suggesting that PDTC may be an effective Nrf2 inducer in the context of Alzheimer’s disease. Finally, we show that PDTC increases brain copper content and glial expression of heme oxygenase-1, and decreases lipid peroxidation in vivo, promoting a more antioxidative environment.

Conclusions

PDTC activates Nrf2 and its antioxidative targets in astrocytes but not neurons. These effects may contribute to the neuroprotection observed for PDTC in models of Alzheimer’s disease.
Appendix
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Metadata
Title
Pyrrolidine dithiocarbamate activates the Nrf2 pathway in astrocytes
Authors
Jeffrey R. Liddell
Sarka Lehtonen
Clare Duncan
Velta Keksa-Goldsteine
Anna-Liisa Levonen
Gundars Goldsteins
Tarja Malm
Anthony R. White
Jari Koistinaho
Katja M. Kanninen
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2016
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-016-0515-9

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