N‐methyl‐N‐nitrosourea induces retinal degeneration in the rat via the inhibition of NF‐κB activation

Abstract

Retinitis pigmentosa (RP) is a group of inherited neurodegenerative diseases characterized by the loss of photoreceptor cells through apoptosis. N-methyl-N-nitrosourea (MNU) is an alkylating toxicant that induces photoreceptor cell death resembling hereditary RP. This study aimed to investigate the role of nuclear factor κB (NF-κB) in MNU-induced photoreceptor degeneration. Adult rats received a single intraperitoneal injection of MNU (60 mg/kg bodyweight). Hematoxylin and eosin staining demonstrated progressive outer nuclear layer (ONL) loss after MNU treatment. Transmission electron microscopy revealed nuclear pyknosis, chromatin margination in the photoreceptors, increased secondary lysosomes, and lobulated retinal-pigmented epithelial cells in MNU-treated rats. Numerous photoreceptor cells in the ONL showed positive TUNEL staining and apoptosis rate peaked at 24 hours. Enhanced depth imaging spectral-domain optical coherence tomography showed ONL thinning and decreased choroid thickness. Electroretinograms showed decreased A wave amplitude that predominated in scotopic conditions. Western blot analysis showed that nuclear IκBα level increased, whereas nuclear NF-κB p65 decreased significantly in the retinas of MNU-treated rats. These findings indicate that MNU leads to selective photoreceptor degradation, and this is associated with the inhibition of NF-κB activation.

miRNAexpression profile of retinal pigment epithelial cells under oxidative stress conditions

“…However, because it is the only down‐expressed miRNA throughout all the time points, its role might be considered less decisive than the others. Therefore, a possible dysregulation of the nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) signaling pathway emerged, a pathway already associated to retinal degeneration , along with fatty acid metabolism, known to be one of the most involved pathways in RP and its particular forms, such as Stargardt syndrome . Moreover, several new interesting pathways could be altered by the analyzed miRNAs, as emerged from target gene predictions.…”

Otx2 enhances transdifferentiation of Müller cells‐derived retinal stem cells into photoreceptor‐like cells

“…Photoreceptor degeneration rat model was established and validated by intraperitoneal injection of 60 mg/Kg MNU as previously described . After subretinal injection of differentiated MC‐RSCs into photoreceptor degeneration rat model, the total thickness of retina at 14 days and 28 days in Otx2 group was 91.62 ± 15.27 μm and 118.06 ± 21.42 μm, respectively, significantly thicker than that of the time of injection (63.21 ± 6.92 μm), while the total thickness of retina in model group and GFP group had no obvious change (Figure A).…”

“…On the basis of these data, we added RA and taurine into the differentiation medium to improve the differentiation efficiency of photoreceptor‐like cells. To evaluate the in vivo differentiation of Otx2 induced MC‐RSCs, we employed MNU‐induced photoreceptor degeneration rat model as established previously . The subretinal cavity is recognized as immune privileged region, and cell transplantation has advantages such as the low immune rejection and less systemic adverse reactions .…”

“…MNU (Aladdin; N136701, Shanghai, China) was stored at −20°C in the dark and dissolved into saline containing 0.05% acetic acid immediately prior to use. Female Sprague‐Dawley rats (6 weeks old) were treated with ip, dose of sterile MNU (60 mg/kg body weight) as described previously . Rats were maintained at 22 ± 2°C and 60 ± 10% humidity with a 12:12 hours light/dark cycle with free access to the food and water.…”

Molecular Hydrogen Attenuated N-methyl-N-Nitrosourea Induced Corneal Endothelial Injury by Upregulating Anti-Apoptotic Pathway

“…As an alkylating agent that directly acts on DNA, it is widely believed that it can induce apoptosis of cells, [12][13][14] including eye cells. 15,16 Hayakawa and coworkers have shown that MNU can affect a variety of eye cells, resulting in continuous ultrastructural changes. 17 With significant corneal edema in a dose-and time-dependent way, our model could simulate the natural process of corneal endothelial injury to a certain extent.…”