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Dopamine activates Nrf2-regulated neuroprotective pathways in astrocytes and meningeal cells

By Andy Y. Shih, Heidi Erb and Timothy H. Murphy

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 mitoch-ondrial 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 dop-amine release can act as an endogenous Nrf2-inducing sig-nal. 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 neurotrans-mitters 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 neurode-generation

Topics: tertiary-butylhydroquinone, antioxidant response element, glutathione, ischemia, Phase 2 enzymes, Keap1
Year: 2007
OAI identifier: oai:CiteSeerX.psu:10.1.1.489.5056
Provided by: CiteSeerX
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