Omega-3 Fatty Acid and its Metabolite 18-HEPE Ameliorate Retinal Neuronal Cell Dysfunction by Enhancing Müller BDNF in Diabetic Retinopathy.

Diabetic retinopathy (DR) is a widespread vision-threatening disease, and neuroretinal abnormality should be considered as an important problem. Brain-derived neurotrophic factor (BDNF) has recently been considered as a possible treatment to prevent DR-induced neuroretinal damage but how BDNF is upregulated in DR remains unclear. We found increase in hydrogen peroxide (H2O2) in the vitreous of patients with DR. We confirmed that human retinal endothelial cells secreted H2O2 by high glucose and H2O2 reduced cell viability of MIO-M1, Muller glia cell line, and PC12D, neuronal cell line, and lowered BDNF expression in MIO-M1, whereas BDNF administration recovered PC12D cell viability. Streptozocin (STZ)-induced diabetic rats showed reduced BDNF, which is mainly expressed in the Muller glia cell. Oral intake of Eicosapentaenoic acid ethyl ester (EPA-E) ameliorated BDNF reduction and oscillatory potentials (OPs) in electroretinography (ERG) in DR. Mass spectrometry revealed increase in several EPA metabolites in the eyes of EPA-E-fed rats. In particular, an EPA metabolite 18-hydroxyeicosapentaenoic acid (18-HEPE) induced BDNF upregulation in Muller glia cells and recovery of OPs in ERG. Our results indicated diabetes-induced oxidative stress attenuates neuroretinal function, but oral EPA-E intake prevents retinal neurodegeneration via BDNF in Muller glia cells by increasing 18-HEPE in the early-stages of DR.