Monomethyl Fumarate Protects the Retina From Light-Induced Retinopathy

• Published in: Investigative ophthalmology & visual science Vol. 60; no. 4; pp. 1275 - 1285
• Main Authors: Jiang, Dan, Ryals, Renee C, Huang, Samuel J, Weller, Kyle K, Titus, Hope E, Robb, Bryan M, Saad, Firas W, Salam, Ribal A, Hammad, Hytham, Yang, Paul, Marks, Daniel L, Pennesi, Mark E
• Format: Journal Article
• Language: English
• Published: United States The Association for Research in Vision and Ophthalmology 01.03.2019
• Subjects: Animals; Blotting, Western; Dermatologic Agents - therapeutic use; Electroretinography; Fumarates - therapeutic use; Gene Expression Regulation - physiology; Light - adverse effects; Male; Maleates - therapeutic use; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2 - genetics; NF-kappa B - genetics; Radiation Injuries, Experimental - diagnostic imaging; Radiation Injuries, Experimental - etiology; Radiation Injuries, Experimental - physiopathology; Radiation Injuries, Experimental - prevention & control; Radiation-Protective Agents - therapeutic use; Real-Time Polymerase Chain Reaction; Receptors, G-Protein-Coupled - genetics; Retina; Retina - diagnostic imaging; Retina - physiopathology; Retina - radiation effects; Retinal Degeneration - diagnostic imaging; Retinal Degeneration - etiology; Retinal Degeneration - physiopathology; Retinal Degeneration - prevention & control; Tomography, Optical Coherence
• ISSN: 1552-5783; 0146-0404; 1552-5783
• DOI: 10.1167/iovs.18-24398

We determine if monomethyl fumarate (MMF) can protect the retina in mice subjected to light-induced retinopathy (LIR). Albino BALB/c mice were intraperitoneally injected with 50 to 100 mg/kg MMF before or after exposure to bright white light (10,000 lux) for 1 hour. Seven days after light exposure, retinal structure and function were evaluated by optical coherence tomography (OCT) and electroretinography (ERG), respectively. Retinal histology also was performed to evaluate photoreceptor loss. Expression levels of Hcar2 and markers of microglia activation were measured by quantitative PCR (qPCR) in the neural retina with and without microglia depletion. At 24 hours after light exposure, retinal sections and whole mount retinas were stained with Iba1 to evaluate microglia status. The effect of MMF on the nuclear factor kB subunit 1 (NF-kB) and Nrf2 pathways was measured by qPCR and Western blot. MMF administered before light exposure mediated dose-dependent neuroprotection in a mouse model of LIR. A single dose of 100 mg/kg MMF fully protected retinal structure and function without side effects. Expression of the Hcar2 receptor and the microglia marker Cd14 were upregulated by LIR, but suppressed by MMF. Depleting microglia reduced Hcar2 expression and its upregulation by LIR. Microglial activation, upregulation of proinflammatory genes (Nlrp3, Caspase1, Il-1β, Tnf-α), and upregulation of antioxidative stress genes (Hmox1) associated with LIR were mitigated by MMF treatment. MMF can completely protect the retina from LIR in BALB/c mice. Expression of Hcar2, the receptor of MMF, is microglia-dependent in the neural retina. MMF-mediated neuroprotection was associated with attenuation of microglia activation, inflammation and oxidative stress in the retina.