Abstract
Purpose :
Dimethyl fumarate (DMF), a fumaric acid ester (FAE) compound that activates Nrf2, has recently been approved for the treatment of multiple sclerosis, based on its neuroprotective and anti-inflammatory effects. Our lab has shown a neuroprotective role for MMF, the primary metabolite of DMF, by demonstrating ERG b-wave recovery in retina in the mouse model of ischemia-reperfusion (I/R). The objective of this study was to determine if MMF exerts anti-inflammatory effects and reduces Müller cell gliosis in the mouse I/R model and the role of Nrf2 in mediating MMF action.
Methods :
Retinal I/R was performed by elevating intraocular pressure to 90mmHg for 90 min. Wild-type and Nrf2 knockout mice were compared to assess the impact of Nrf2 loss of function. Mice were pre-treated with intraperitoneal injections of MMF or vehicle at 2 days, 1 day and 0 day before I/R. After I/R, mice were treated daily with MMF or vehicle until sacrificed at designated time points. Inflammatory gene expression was determined at 48 hrs after I/R. At 7 days, GFAP immunofluorescence was used to determine Müller cell gliosis.
Results :
Forty-eight hours after I/R injury, MMF treatment significantly suppressed the expression of a battery of inflammatory genes in wild-type mice. Seven days after I/R, a significant increase in Müller cell gliosis was observed in the vehicle-treated group. This I/R-induced increase was significantly suppressed by MMF treatment. Importantly, MMF treatment did not show these effects in Nrf2 knockout mice, suggesting that these MMF effects were Nrf2-specific.
Conclusions :
The results from this study indicate that MMF exerts an anti-inflammatory effect and reduces Müller cell gliosis in the retinal ischemia-reperfusion model in an Nrf2-dependent manner. Given that many major retinal diseases are associated with reactive Müller cell gliosis, these treatment effects of MMF could have broad implications for the treatment of multiple retinal pathologies
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.