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

Abstract

Diabetic retinopathy (DR) is a widespread visionthreatening 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 an increase in hydrogen peroxide (H 2 O 2 ) in the vitreous of patients with DR. We confirmed that human retinal endothelial cells secreted H 2 O 2 by high glucose, and H 2 O 2 reduced cell viability of MIO-M1, Müller glia cell line, PC12D, and the neuronal cell line and lowered BDNF expression in MIO-M1, whereas BDNF administration recovered PC12D cell viability. Streptozocin-induced diabetic rats showed reduced BDNF, which is mainly expressed in the Müller 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 an 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 Müller 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 Müller glia cells by increasing 18-HEPE in the early stages of DR.

Protective Effects and Molecular Signaling of n-3 Fatty Acids on Oxidative Stress and Inflammation in Retinal Diseases

“…A single EPA administration improved vascular endothelial function in type 2 diabetic Otsuka Long-Evans Tokushima fatty rats by inhibiting ERK, decreasing NF-κB activation, and reducing COX-2 expression [ 164 ]. In addition, oral EPA administration alleviated retinal neurodegeneration via BDNF in Müller glia cells in the early DR stages [ 162 ]. Clinically, a randomized controlled trial conducted in patients with diabetic macular edema (DME), which was induced by ROS and DR inflammation, found that the combined administration of oral DHA and intravitreal anti-VEGF significantly improved DME compared with a single treatment with anti-VEGF drugs.…”

Melatonin exerts neuroprotective effects by inhibiting neuronal pyroptosis and autophagy in STZ‐induced diabetic mice

“…1 DM is associated with severe damage to multiple organ systems, such as the heart, eyes, and kidneys. [2][3][4] Recently, increasing attention has been paid to the pathological changes in the brain induced by DM. Diabetes-induced brain injury manifests as neurodegeneration, cerebral infarction, and progressive cognitive decline.…”

Effect of Periodontal Disease on Diabetic Retinopathy in Type 2 Diabetic Patients: A Cross-Sectional Pilot Study

“…The involvement of reactive oxygen species (ROS) is considered to be a factor in which inflammation of the gingiva affected diabetic retinopathy [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ]. Porphyromonas gingivalis ( P. gingivalis ) and Fusobacterium nucleatum ( F .…”

“…Overproduced ROS in the oral cavity can cause oxidative stress and oxidative damage to cells, proteins, and lipids throughout the body, which can lead to systemic disease [ 31 ]. Oxidative stress has been shown to reduce neuroretinal function [ 32 ]. In addition, oxidative stress has been found to be associated with the accelerated onset of diabetic retinopathy [ 33 ].…”