Monomethyl fumarate protects the retina in a mouse model of light-induced retinal degeneration

Abstract

Purpose : Monomethy fumarate (MMF) is the biologically active metabolite of dimethyl fumarate (DMF), which has been FDA-approved for treating multiple sclerosis. MMF targets a profile of molecules implicated in geographic atrophy (GA) and inherited retinal degenerations. We studied the ability of MMF to elicit retinal neuroprotection using a mouse model of light-induced retinal degeneration (LIRD).

Methods : LIRD was induced by exposing albino BALB/c mice (8-10 weeks old male) to bright light (10,000 lux) for 1 hour. Before light exposure, MMF at doses ranging from 50 mg/kg to 100 mg/kg, or the same volume of 1xPBS as the vehicle, were injected intraperitoneally into BALB/c mice (n>9 in each group). Seven days after light exposure and injection, spectral domain optical coherence tomography (SD-OCT) and electroretinography (ERG) were used to evaluate the retina structure and function. Real-time quantitative PCR was used to assess gene expression level changes in the neural retinas (n=6 per group) at 24 hours post-light exposure. One-way ANOVA (with Tukey’s multiple comparison tests) was used for statistical analysis among different groups.

Results : MMF significantly protected mouse retina from LIRD, both structurally and functionally. MMF-mediated retinal protection was dose-dependent, starting from a single dose of 50 mg/kg to ranging up to 100 mg/kg, which provided full protection without side effects. At 24 hours post-light exposure, the expression of the Hcar2 receptor, macrophages/microglia markers (Cd14, Cxcl11, Mrc1, Ccl22), proinflammatory genes (Nlrp3, Casp1, Il-1β, Tnf-α), and an anti-oxidative gene (Hmox1) were upregulated. Treatment with 100 mg/kg of MMF significantly attenuated or reversed the gene changes caused by LIRD.

Conclusions : This study provided evidence that MMF can completely protect the retina from LIRD in BALB/c mice. MMF-mediated neuroprotection involved modulation of genes associated with macrophage/microglia activation, oxidative stress, and inflammation. The neuroprotective effects suggested MMF as a potential candidate for the treatment of GA or inherited retinal degenerations.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.