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

J Neurochem. 2015 Apr;133(2):233-41. doi: 10.1111/jnc.13064. Epub 2015 Mar 4.


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.

Keywords: Nrf2; ganglion cell; ischemia; oxidative stress; retina.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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