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Hongkwan Cho, Zhenhua Xu, Matthew J Hartsock, Junsong Gong, Yanhong Wei, Elia J Duh; Monomethyl fumarate prevents neuronal cell death in retinal ischemia-reperfusion. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):20. doi: https://doi.org/.
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Nrf2 is known to play a cytoprotective role in multiple disease settings. Our lab and others have demonstrated the beneficial role of Nrf2 in retinal conditions including ischemia-reperfusion and diabetic retinopathy. The objective of this study was to explore the neuroprotective role of Nrf2 using genetic loss of function studies and to determine if the Nrf2 activator monomethyl fumarate (MMF) can reduce neurodegeneration in the mouse ischemia-reperfusion model.
Wild-type and Nrf2 null mice were compared for loss of function studies. Primary retinal ganglion cells were isolated by an immunopanning technique, and cell viability determined four days after purification and culture. Retinal ischemia-reperfusion (I/R) model was performed by elevating intraocular pressure to 90mmHg for 90 min. For therapeutic studies, mice were pretreated with intraperitoneal injections of MMF or vehicle at 2 days, 1 day and 0 day before IR. Mice were treated daily with MMF or PBS for 6 days after IR. At seven days after I/R injury, NeuN immunostaining of retina flat-mounts was used to determine cell loss in the ganglion cell layer. Retinal function was measured by scotopic electroretinogram (ERG).
Primary ganglion cells from Nrf2 knockout mice exhibited significantly reduced cell viability compared to wild-type cells. Nrf2 knockout mice exhibited greater cell loss in the ganglion cell layer compared to Nrf2 knockout mice. Seven days after I/R injury, significant cell loss was observed in the ganglion cell layer (GCL) in the vehicle-treated group. MMF treatment significantly increased cell survival after I/R, resulting in marked reduction of cell loss in the GCL. Scotopic ERG b-wave amplitude was significantly impaired in the IR eyes compared to the contralateral eyes, which was partially rescued by MMF treatment.
These results indicate that Nrf2 plays an important retinal neuroprotective role. Therapy with the Nrf2 activator MMF exerts a neuronal protective function in the retinal ischemia-reperfusion model. MMF could therefore be a potential therapeutic agent for retinal diseases associated with neurodegeneration.
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