Pyrrolidine dithiocarbamate activates the Nrf2 pathway in astrocytes View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-02-26

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

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. More... »

PAGES

49

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12974-016-0515-9

DOI

http://dx.doi.org/10.1186/s12974-016-0515-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1028134990

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26920699


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40 Nrf2
41 Nrf2 inducers
42 Nrf2 induction
43 Nrf2 pathway
44 Nrf2 signaling
45 Nrf2-deficient cultures
46 PDTC-mediated induction
47 activator
48 amyloid-beta magnifies PDTC-mediated induction
49 antioxidative environment
50 antioxidative targets
51 astrocytes
52 brain
53 brain copper content
54 cells
55 chelators
56 compensatory mechanisms
57 content
58 context
59 copper content
60 critical role
61 culture
62 cultured astrocytes
63 defense
64 defense mechanisms
65 disease
66 disease models
67 dithiocarbamate
68 effect
69 effective Nrf2 inducer
70 endogenous defense
71 endogenous defense mechanisms
72 endogenous protective mechanism
73 environment
74 exposure
75 expression
76 factor 2
77 factor-κB inhibitor pyrrolidine dithiocarbamate
78 factors
79 glial expression
80 heme oxygenase-1
81 inducer
82 induction
83 inhibitor pyrrolidine dithiocarbamate
84 inhibitors
85 kinase-3β
86 lipid peroxidation
87 magnifies PDTC-mediated induction
88 mechanism
89 metal chelators
90 model
91 mouse brain
92 neurons
93 neuroprotection
94 normal compensatory mechanisms
95 nuclear factor
96 nuclear factor-κB inhibitor pyrrolidine dithiocarbamate
97 oxidative stress
98 oxygen species
99 oxygenase-1
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101 peroxidation
102 potent inducer
103 presence
104 prolonged exposure
105 protection
106 protective mechanism
107 pyrrolidine dithiocarbamate
108 role
109 signaling
110 small molecule activators
111 species
112 stimulation
113 stimulation of Nrf2
114 strategies
115 stress
116 synthase kinase-3β
117 target
118 vivo
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