Tauroursodeoxycholic acid protects retinal pigment epithelial cells from oxidative injury and endoplasmic reticulum stress in vitro

Retinal degeneration is characterized by the dysfunction of retinal cells. Oxidative and endoplasmic reticulum (ER) stress play an important role in the pathogenesis and progression of retinal degeneration. Tauroursodeoxycholic acid (TUDCA) has been demonstrated to have protective effects in in vitro and in vivo retinal degeneration models. To fully understand the molecular mechanisms of TUDCA’s protection, we first treated human retinal pigment epithelial (RPE) cells, ARPE-19, with H2O2 or H2O2 plus TUDCA for 24 h. RPE cells co-exposed to TUDCA had higher cell viability and lower cell death rate compared to cells exposed to H2O2 alone. TUDCA significantly increased antioxidant capacity in H2O2-treated RPE cells by decreasing the generation of reactive oxygen species (ROS) and Malondialdehyde (MDA), upregulating the expression of antioxidant genes, and increasing the generation of glutathione (GSH). TUDCA also inhibited inflammation in H2O2-challenged RPE cells by decreasing the expression of proinflammatory cytokines. Furthermore, TUDCA suppressed thapsigargin-induced ER stress in RPE cells, as demonstrated by decreased the expression of CCAAT-enhancer-binding protein homologous protein (CHOP) and apoptosis. Our present study suggests that TUDCA can protect RPE cells against oxidative damage, inflammation, and ER stress and may benefit patients with retinal degeneration

Deletion of TSPO causes dysregulation of cholesterol metabolism in mouse retina

Cholesterol dysregulation has been implicated in age-related macular degeneration (AMD), the most common cause of visual impairment in the elderly. The 18 KDa translocator protein (TSPO) is a mitochondrial outer membrane protein responsible for transporting cholesterol from the mitochondrial outer membrane to the inner membrane. TSPO is highly expressed in retinal pigment epithelial (RPE) cells, and TSPO ligands have shown therapeutic potential for the treatment of AMD. Here, we characterized retinal pathology of Tspo knockout (KO) mice using histological, immunohistochemical, biochemical and molecular biological approaches. We found that Tspo KO mice had normal retinal morphology (by light microscopy) but showed elevated levels of cholesterol, triglycerides and phospholipids with perturbed cholesterol efflux in the RPE cells of Tspo KO mice. Expression of cholesterol-associated genes (Nr1h3, Abca1, Abcg1, Cyp27a1 and Cyp46a1) was significantly downregulated, and production of pro-inflammatory cytokines was markedly increased in Tspo KO retinas. Furthermore, microglial activation was also observed in Tspo KO mouse retinas. These findings provide new insights into the function of TSPO in the retina and may aid in the design of new therapeutic strategies for the treatment of AMD

Toxicity of a seafood toxin, domoic acid, in the retina via modulation of the NRF2 and NF-κB pathways

Domoic acid (DA), a biotoxin, is produced by several species of marine dinoflagellate and diatom during harmful algal bloom events. DA is a neurotoxin, in humans and non-human primates, oral exposure to DA results in gastrointestinal effects, while DA at higher doses leads to neurological symptoms, seizures and memory deficiency. Exposure of humans to DA occurs mainly through consumption of contaminated seafoods containing an accumulation of the toxin. Previously, it was unclear if DA can have toxic effects on the retina. We assessed the toxicity of DA in human retinal cells (ARPE-19) and in zebrafish embryos. DA significantly lowered ARPE-19 cell viability dose-dependently, and decreased anti-oxidative capacity, increased inflammation, and promoted cell death, possibly through modulating the NRF2 and NF-κB signalling pathways. Zebrafish embryos exposed to DA for four days from one day post fertilization (dpf) had an increase in mortality and a decrease in both hatching and heartbeat rate and exhibited morphological abnormalities. DA treatment also significantly downregulated expression of antioxidant genes and upregulated expression of inflammation mediators, as well as causing photoreceptor death in zebrafish embryos. The results demonstrate that consuming seafood containing DA will have potential toxic effects in human retinas