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Pyrrolidine dithiocarbamate activates the Nrf2 pathway in astrocytes
Jeffrey R Liddell1,2, Sarka Lehtonen3, Clare Duncan4,5
1Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. jliddell@unimelb.edu.au.
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.
Insights
Pyrrolidine dithiocarbamate (PDTC) activates the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in astrocytes, enhancing cellular defense against oxidative stress and showing potential for Alzheimer's disease treatment.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Oxidative stress is implicated in neurodegenerative diseases like Alzheimer's.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of endogenous antioxidant defenses.
- Current antioxidant mechanisms are often insufficient against prolonged oxidative insult.
Purpose of the Study:
- To investigate the Nrf2-inducing potential of pyrrolidine dithiocarbamate (PDTC).
- To explore PDTC's efficacy in astrocytes and neurons under conditions relevant to Alzheimer's disease.
- To elucidate the mechanisms underlying PDTC-mediated Nrf2 activation.
Main Methods:
- Investigated Nrf2 induction by PDTC in cultured astrocytes and neurons.
- Examined Nrf2 response in co-cultures with amyloid-beta and kinase inhibitors.
- Utilized Nrf2-deficient cell cultures for mechanistic studies.
- Assessed in vivo effects in mouse brain.
Main Results:
- PDTC potently induces Nrf2 signaling specifically in astrocytes.
- Nrf2 plays a critical role in PDTC's protection against oxidative stress.
- Amyloid-beta enhances PDTC-mediated Nrf2 induction.
- PDTC increases brain copper and heme oxygenase-1, reducing lipid peroxidation in vivo.
Conclusions:
- PDTC activates Nrf2 and its antioxidant targets in astrocytes, but not neurons.
- These findings suggest PDTC's potential neuroprotective role in Alzheimer's disease models.
