Activation of the Keap1/Nrf2 Pathway for Neuroprotection by Electrophillic Phase II Inducers

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 3; pp. 768 - 773
• Main Authors: Satoh, T., Okamoto, S.-i., Cui, J., Watanabe, Y., Furuta, K., Suzuki, M., Tohyama, K., Lipton, S. A.
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 17-01-2006; National Acad Sciences
• Series: From the Cover
• Subjects: Antibodies; Antioxidants; Biological Sciences; Cell lines; Enzymes; Neurology; Neurons; Neuroprotectants; Neuroscience; Oxidation; Prostaglandins; Stroke; Thiols; Toxicity; Vehicles
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0505723102

Electrophilic neurite outgrowth-promoting prostaglandin (NEPP) compounds protect neurons from oxidative insults. At least part of the neuroprotective action of NEPPs lies in induction of hemeoxygenase-1 (HO-1), which, along with other phase II enzymes, serve as a defense system against oxidative stress. Here, we found that, by using fluorescent tags and immunoprecipitation assays, NEPPs are taken up preferentially into neurons and bind in a thiol-dependent manner to Keap1, a negative regulator of the transcription factor Nrf2. By binding to Keap1, NEPPs prevent Keap1-mediated inactivation of Nrf2 and, thus, enhance Nrf2 translocation into the nucleus of cultured neuronal cells. In turn, Nrf2 binds to antioxidant/ electrophile-responsive elements of the HO-1 promoter to induce HO-1 expression. Consistent with this notion, NEPP induction of an HO-1 reporter construct is prevented if the antioxidant-responsive elements are mutated. We show that NEPPs are neuroprotective both in vitro from glutamate-related excitotoxicity and in vivo in a model of cerebral ischemia/reperfusion injury (stroke). Our results suggest that NEPPs prevent excitotoxicity by activating the Keap1/Nrf2/HO-1 pathway. Because NEPPs accumulate preferentially in neurons, they may provide a category of neuroprotective compounds, distinct from other electrophilic compounds such as tertbutylhydroquinone, which activates the antioxidant-responsive element in astrocytes. NEPPs thus represent a therapeutic approach for stroke and neurodegenerative disorders.