title: Monomethyl fumarate promotes Nrf2-dependent neuroprotection in retinal ischemia-reperfusion.
abstract: BACKGROUND
  Retinal ischemia results in neuronal degeneration and contributes to the pathogenesis of multiple blinding diseases. Recently, the fumaric acid ester dimethyl fumarate (DMF) has been FDA-approved for the treatment of multiple sclerosis, based on its neuroprotective and anti-inflammatory effects. Its potential role as a neuroprotective agent for retinal diseases has received little attention. In addition, DMF's mode of action remains elusive, although studies have suggested nuclear factor erythroid 2-related factor 2 (Nrf2) activation as an important mechanism. Here we investigated the neuroprotective role of monomethyl fumarate (MMF), the biologically active metabolite of DMF, in retinal ischemia-reperfusion (I/R) injury, and examined the role of Nrf2 in mediating MMF action.
  
  
  METHODS
  Wild-type C57BL/6J and Nrf2 knockout (KO) mice were subjected to 90 min of retinal ischemia followed by reperfusion. Mice received daily intraperitoneal injection of MMF. Inflammatory gene expression was measured using quantitative reverse transcription PCR (qRT-PCR) at 48 h after I/R injury. Seven days after I/R, qRT-PCR for Nrf2 target gene expression, immunostaining for Müller cell gliosis and cell loss in the ganglion cell layer (GCL), and electroretinography for retinal function were performed.
  
  
  RESULTS
  The results of this study confirmed that MMF reduces retinal neurodegeneration in an Nrf2-dependent manner. MMF treatment significantly increased the expression of Nrf2-regulated antioxidative genes, suppressed inflammatory gene expression, reduced Müller cell gliosis, decreased neuronal cell loss in the GCL, and improved retinal function measured by electroretinogram (ERG) after retinal I/R injury in wild-type mice. Importantly, these MMF-mediated beneficial effects were not observed in Nrf2 KO mice.
  
  
  CONCLUSIONS
  These results indicate that fumaric acid esters (FAEs) exert a neuronal protective function in the retinal I/R model and further validate Nrf2 modulation as a major mode of action of FAEs. This suggests that DMF and FAEs could be a potential therapeutic agent for activation of the Nrf2 pathway in retinal and possibly systemic diseases.
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA. hongkwancho@jhmi.edu.
authors.forename: Hongkwan
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA. Matthew.Hartsock@colorado.edu.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Hartsock
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA. zxu6@jhmi.edu.
authors.forename: Zhenhua
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA. hemeihua@bjmu.edu.cn.
authors.forename: Meihua
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Ophthalmology, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA. eduh@jhmi.edu.
authors.forename: Elia J
authors.initials: EJ
authors.lastname: Duh
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004596:Electroretinography; D005650:Fumarates / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D012162:Retinal Degeneration / Q000378:metabolism / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D005650:Fumarates; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495636:Nfe2l2 protein, mouse