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Published on: April 24, 2013
Dopamine activates Nrf2-regulated neuroprotective pathways in astrocytes and meningeal cells
Andy Y Shih1, Heidi Erb, Timothy H Murphy
1Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada.
Abstract:
The transcription factor Nrf2 controls inducible expression of multiple antioxidant/detoxification genes. We previously found that Nrf2-/- mice have increased sensitivity to in vivo mitochondrial stress and ischemia. Although Nrf2 regulated these forms of neuronal toxicity, it was unclear which injury-triggered signal(s) led to Nrf2 activation in vivo. In this study, we use primary cultures to test the hypothesis that excessive dopamine release can act as an endogenous Nrf2-inducing signal. We cultured two cell types that show increased Nrf2 activity during ischemia in vivo, astrocytes and meningeal cells. Cultures were infected with an adenovirus reporter of Nrf2 transcriptional activity. Dopamine-induced Nrf2 activity in both cell types by generating oxidative stressors, H2O2 and dopamine-quinones. Nrf2 activation in meningeal cells was significantly higher than astrocytes. The effect of dopamine was blocked by antioxidants, and by over-expression of either dominant-negative Nrf2 or Keap1. Nrf2 induction was specific to oxidative stress caused by catecholaminergic neurotransmitters as epinephrine also induced Nrf2, but the monoamine serotonin had no significant effect. These in vitro results suggest Nrf2 activity in astrocytes and meningeal cells link the neurotoxic actions of dopamine to neuroprotective pathways that may potentially modulate ischemic injury and neurodegeneration.
Insights
Excessive dopamine release activates the Nrf2 pathway, enhancing cellular defense against oxidative stress. This finding links dopamine signaling to neuroprotection, potentially impacting neurodegenerative diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- The transcription factor Nrf2 regulates antioxidant and detoxification genes.
- Nrf2-deficient mice exhibit heightened sensitivity to mitochondrial stress and ischemia.
- The specific in vivo signals triggering Nrf2 activation during injury remained unclear.
Purpose of the Study:
- To investigate if excessive dopamine release acts as an endogenous signal for Nrf2 activation.
- To explore the role of dopamine in modulating Nrf2 activity in astrocytes and meningeal cells.
Main Methods:
- Primary astrocyte and meningeal cell cultures were utilized.
- An adenovirus reporter system measured Nrf2 transcriptional activity.
- Cells were exposed to dopamine and other catecholamines to assess Nrf2 induction.
Main Results:
- Dopamine induced Nrf2 activity in both astrocytes and meningeal cells by generating oxidative stressors like H2O2 and dopamine-quinones.
- Nrf2 activation was significantly higher in meningeal cells compared to astrocytes.
- Dopamine's effect was abrogated by antioxidants and by manipulating Nrf2 and Keap1 expression.
- Epinephrine also induced Nrf2, while serotonin did not.
Conclusions:
- Dopamine acts as an endogenous Nrf2-inducing signal, mediated by oxidative stress.
- Nrf2 activation in astrocytes and meningeal cells connects dopamine's neurotoxic potential to neuroprotective mechanisms.
- This pathway may play a role in modulating ischemic injury and neurodegeneration.
