Abstract
This study aimed to verify whether dimethyl fumarate (DMF) promotes the survival of retinal ganglion cells (RGCs) after optic nerve crush (ONC) accompanied by activation of the NF-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. We examined changes in the densities of tubulin β3 (TUBB3)-positive RGCs and the amplitudes of the positive scotopic threshold response (pSTR), reflecting the functional activity of RGCs, recorded on an electroretinogram, with daily administration of DMF, on day 7 after ONC. Furthermore, immunohistochemical and immunoblotting analyses were performed to study the activation of the Nrf2/HO-1 pathway using retinas treated with daily administration of DMF. Daily administration of DMF increasedthe density of TUBB3-positive RGCs in a dose-dependent fashion and significantly increased the amplitude of the pSTR. Immunohistochemical analysis showed that DMF administration increased the immunoreactivity for Nrf2 and HO-1, a potent antioxidant enzyme, in RGCs immunolabeled with RNA-binding protein with multiple splicing (RBPMS). Immunoblotting analysis revealed an increase in the nuclear expression of Nrf2 and marked upregulation of HO-1 after DMF administration. These results suggest that DMF has survival-promoting effects in RGC after ONC, possibly via the Nrf2/HO-1 pathway.
Highlights
Retinas with optic nerve crush (ONC) plus the vehicle exhibited a decrease in the number of surviving TUBB3-positive cells, dimethyl fumarate (DMF) administration obviously increased TUBB3-positive cells (Figure 1A)
DMF administration significantly increased the mean densities of TUBB3-positive cells at
To verify whether DMF administration augmented retinal ganglion cells (RGCs) survival and their functions after ONC, we examined the changes in the positive scotopic threshold response, which reflects the activity of RGCs using the most effective concentration of DMF for promoting their survival
Summary
Dimethyl fumarate (DMF) and its derivative, monomethyl fumarate (MMF), were used as oral medications against psoriasis, chronic dermatitis, and multiple sclerosis; their safety and effectiveness against these diseases have been established [1,2]. DMF is rapidly degraded to MMF, which is absorbed in the digestive tract. Previous studies using an animal model of experimental allergic encephalomyelitis (EAE) or cerebral vascular disturbance have shown that the pharmacological effects of DMF are mainly antioxidative and immune modulating. The Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2) pathway has been suggested to play a critical role in the antioxidant effects of DMF [3,4]. The cytosolic Nrf protein constantly binds to Keap under physiological conditions. Under stress conditions, Nrf dissociates from Keap and is transferred to the nucleus
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