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Updated: Mar 28, 2026
A Mouse Model of Retinal Ischemia-Reperfusion Injury Through Elevation of Intraocular Pressure
Published on: July 14, 2016
Monomethyl fumarate promotes Nrf2-dependent neuroprotection in retinal ischemia-reperfusion
Hongkwan Cho1, Matthew J Hartsock2, Zhenhua Xu3
1Department of Ophthalmology, Johns Hopkins University School of Medicine, 400 N. Broadway, Baltimore, MD, 21287, USA. hongkwancho@jhmi.edu.
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.
Insights
Monomethyl fumarate (MMF) protects against retinal ischemia-reperfusion injury by activating the Nrf2 pathway. This neuroprotective effect, observed in wild-type mice, was absent in Nrf2 knockout mice, highlighting Nrf2
Area of Science:
- Neuroscience
- Ophthalmology
- Pharmacology
Background:
- Retinal ischemia causes neuronal degeneration, contributing to blinding diseases.
- Dimethyl fumarate (DMF), an FDA-approved drug, has known neuroprotective and anti-inflammatory effects.
- The neuroprotective role of DMF and its metabolite, monomethyl fumarate (MMF), in retinal diseases is understudied, with Nrf2 activation proposed as a key mechanism.
Purpose of the Study:
- To investigate the neuroprotective potential of MMF in a mouse model of retinal ischemia-reperfusion (I/R) injury.
- To elucidate the role of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in mediating MMF's effects.
Main Methods:
- Retinal I/R injury was induced in wild-type and Nrf2 knockout mice.
- Mice received daily intraperitoneal injections of MMF.
- Evaluated inflammatory gene expression, Nrf2 target gene expression, Müller cell gliosis, neuronal cell loss, and retinal function via electroretinography (ERG).
Main Results:
- MMF significantly reduced neurodegeneration, suppressed inflammation, and improved retinal function in wild-type mice post-I/R.
- MMF increased the expression of Nrf2-regulated antioxidative genes.
- These beneficial effects of MMF were abolished in Nrf2 knockout mice, confirming an Nrf2-dependent mechanism.
Conclusions:
- Fumaric acid esters (FAEs), including MMF, demonstrate neuroprotective effects in retinal I/R injury.
- Nrf2 pathway modulation is a critical mechanism underlying the therapeutic action of FAEs.
- DMF and related FAEs represent potential therapeutic agents for retinal diseases by activating the Nrf2 pathway.
