Neuroprotective role of Nrf2 for retinal ganglion cells in ischemia-reperfusion.

Abstract

Retinal ischemia plays a critical role in multiple vision-threatening diseases and leads to death of retinal neurons, particularly ganglion cells. Oxidative stress plays an important role in this ganglion cell loss. Nrf2 (NF-E2-related factor 2) is a major regulator of the antioxidant response, and its role in the retina is increasingly appreciated. We investigated the potential retinal neuroprotective function of Nrf2 after ischemia-reperfusion (I/R) injury. In an experimental model of retinal I/R, Nrf2 knockout mice exhibited much greater loss of neuronal cells in the ganglion cell layer than wild-type mice. Primary retinal ganglion cells isolated from Nrf2 knockout mice exhibited decreased cell viability compared to wild-type retinal ganglion cells, demonstrating the cell-intrinsic protective role of Nrf2. The retinal neuronal cell line 661W exhibited reduced cell viability following siRNA-mediated knockdown of Nrf2 under conditions of oxidative stress, and this was associated with exacerbation of increase in reactive oxygen species. The synthetic triterpenoid CDDO-Im (2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide), a potent Nrf2 activator, inhibited reactive oxygen species increase in cultured 661W under oxidative stress conditions and increased neuronal cell survival after I/R injury in wild-type, but not Nrf2 knockout mice. Our findings indicate that Nrf2 exhibits a retinal neuroprotective function in I/R and suggest that pharmacologic activation of Nrf2 could be a therapeutic strategy. Oxidative stress is thought to be an important mediator of retinal ganglion cell death in ischemia-reperfusion injury. We found that the transcription factor NF-E2-related factor 2 (Nrf2), a major regulator of oxidative stress, is an important endogenous neuroprotective molecule in retinal ganglion cells in ischemia-reperfusion, exerting a cell-autonomous protective effect.  The triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) reduces neurodegeneration following ischemia-reperfusion in an Nrf2-dependent fashion. This suggests that Nrf2-activating drugs including triterpenoids could be a therapeutic strategy for retinal neuroprotection.

• Authors: Zhenhua Xu, Hongkwan Cho, Matthew J Hartsock, Katherine L Mitchell, Junsong Gong, Lijuan Wu, Yanhong Wei, Shuang Wang, Rajesh K Thimmulappa, Michael B Sporn, Shyam Biswal, Derek S Welsbie, Elia J Duh
• Journal: Journal of neurochemistry (J Neurochem) Vol. 133 Issue 2 Pg. 233-41 (Apr 2015) ISSN: 1471-4159 [Electronic] England
• PMID: 25683606 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 International Society for Neurochemistry.

Chemical References

• 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
• Imidazoles
• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• RNA, Small Interfering
• Reactive Oxygen Species
• Oleanolic Acid
• tert-Butylhydroperoxide

Topics

• Animals
• Cell Survival (genetics)
• Cells, Cultured
• Disease Models, Animal
• Down-Regulation (drug effects, genetics)
• Imidazoles (pharmacology)
• In Vitro Techniques
• Ischemia (pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• NF-E2-Related Factor 2 (genetics, metabolism)
• Oleanolic Acid (analogs & derivatives, pharmacology)
• RNA, Small Interfering (pharmacology)
• Reactive Oxygen Species (metabolism)
• Reperfusion Injury (pathology, prevention & control)
• Retina (cytology)
• Retinal Ganglion Cells (drug effects, metabolism)
• tert-Butylhydroperoxide (pharmacology)