Repurposing dimethyl fumarate? In vitro evidence of Nrf2‐pathway activation and cytoprotective effects in human retinal endothelial cells

References. Nrf2 (NF-E2-related factor 2) pathway is a major defensive system orchestrating cellular response to pro-oxidant and pro-inflammatory stress and regulating the expression of many cytoprotective genes. Pharmacologic activation of Nrf2 has emerged as an attractive strategy for many pathologic conditions. The best-known Nrf2 activator is dimethyl fumarate (DMF), currently used for the treatment of relapsing-remitting multiple sclerosis and psoriasis. However, literature evidence in animal models of eye diseases reports that DMF displays beneficial effects also at ocular level, suggesting its potential therapeutic use also in retinal pathologies. Purpose. The aim of this study was to evaluate in vitro whether DMF activates Nrf2-pathway and exerts beneficial effects in human retinal endothelial cells, and to test its possible cytoprotection against a diabetic retinopathy-related insult. Methods. Human Retinal Endothelial Cells (HREC) were exposed to increasing concentrations of DMF and tested for viability and Nrf2-pathway activation. Expression of Nrf2 and its target HO-1 (Heme Oxygenase-1) coding an antioxidant and detoxifying enzyme relevant for vascular endothelium, were evaluated by Western blotting and real-time quantitative PCR. Intracellular levels of reactive oxygen species (ROS) were investigated after DMF treatment through flow cytometry. DMF-mediated pro-survival effects were also tested in HREC under hyper-glucose conditions. Results. In basal conditions, DMF is optimally tolerated and activates Nrf2/HO-1 pathway, decreasing intracellular ROS levels in HREC. DMF protects HREC under high glucose conditions. Conclusions. Together with the most recent evidence of DMF effects at ocular level, our findings open a new perspective for the repositioning of DMF in eye pathologies involving alterations of the endothelium and, more extensively, for ocular diseases characterized by oxidative stress and inflammation.