Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophilic [correction of electrophillic] phase II inducers.
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 tert-butylhydroquinone, which activates the antioxidant-responsive element in astrocytes. NEPPs thus represent a therapeutic approach for stroke and neurodegenerative disorders.
Satoh
T
T
Center for Neuroscience and Aging, The Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Okamoto
S-i
SI
Cui
J
J
Watanabe
Y
Y
Furuta
K
K
Suzuki
M
M
Tohyama
K
K
Lipton
S A
SA
D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D004790:Enzyme Induction; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D050217:Metabolic Detoxication, Phase II / Q000502:physiology*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D011506:Proteins / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D018696:Neuroprotective Agents; D011506:Proteins; D051547:Heme Oxygenase-1