fumarates and Retinal-Degeneration

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.

Topics: Animals; Blotting, Western; Dermatologic Agents; Electroretinography; Fumarates; Gene Expression Regulation; Light; Male; Maleates; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2; NF-kappa B; Radiation Injuries, Experimental; Radiation-Protective Agents; Real-Time Polymerase Chain Reaction; Receptors, G-Protein-Coupled; Retina; Retinal Degeneration; Tomography, Optical Coherence

Cobalamin C disease (cblC), which leads to methylmalonic acidemia with homocystinuria, is the most common inherited disorder of vitamin B12 metabolism. Reported ocular findings associated with cblC have been maculopathy, pigmentary retinopathy, and optic nerve atrophy. Cobalamin A disease (cblA) which causes an isolated methylmalonic acidemia without homocystinuria is rarer than cblC. This is the first detailed report of the ocular findings associated with cblA. We also describe the spectrum of ocular findings in our cblC patients.. A case series describing the ophthalmologic clinical course of six patients with a diagnosis of cobalamin C type and one patient with cobalamin A type of methylmalonic acidemia. Patients were diagnosed through biochemical laboratory testing and genetic analysis was conducted on most patients. Longitudinal fundus findings, optical coherence tomography (OCT), autofluorescence, and electrophysiology were followed in the patients.. The cblA patient demonstrated a relatively mild ocular phenotype with late-onset and slowly progressing temporal disc pallor and peripapillary atrophy in the second decade of life. The patient maintained good visual acuity and central vision, without evidence of maculopathy. The six cblC patients demonstrated a range of ocular findings from unremarkable and mild phenotypes to significant retinopathy, including bull's eye maculopathy, severe maculopathy with punched out chorioretinal atrophy, peripheral bone spicules, and optic nerve atrophy.. The spectrum of ocular manifestations seen with inherited disorders of cobalamin metabolism is wide, ranging from mild optic nerve atrophy to severe macular or retinal degeneration. This heterogeneity may in part reflect the associated biochemical phenotype, such as that observed between our cblA and cblC patients. We also observed heterogeneity within the cblC type in agreement with previous reports.

Topics: Amino Acid Metabolism, Inborn Errors; Electroretinography; Female; Follow-Up Studies; Fumarates; Homocysteine; Homocystinuria; Humans; Infant; Infant, Newborn; Male; Maleates; Optic Nerve Diseases; Optical Imaging; Retinal Degeneration; Tomography, Optical Coherence; Vision Disorders; Visual Acuity; Vitamin B 12 Deficiency

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.. 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.. 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.. 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.

Topics: Animals; Disease Models, Animal; Electroretinography; Fumarates; Gene Expression Regulation; Immunohistochemistry; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuroprotective Agents; NF-E2-Related Factor 2; Reperfusion Injury; Retinal Degeneration; Retinal Ganglion Cells; Reverse Transcriptase Polymerase Chain Reaction