OBJECTIVEThe aim of this study was to observe the association between N-myc downstream regulated gene 2 (NDRG2)/interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and diabetic retinopathy (DR) in rats.MATERIALS AND METHODSThe model of diabetes was successfully established in Sprague-Dawley rats. All rats were divided into diabetes model group (model group, n=10), pathway inhibitor group (CLT-005 group, n=10), and normal control group (control group, n=10). After successful modeling, blood and retinal tissues of rats were collected. The levels of blood glucose and serum IL-6 were detected. Meanwhile, oxidative and antioxidant indexes reactive oxygen species (ROS), superoxide dismutase (SOD), and malondialdehyde (MDA) were detected via enzyme-linked immunosorbent assay (ELISA). Morphological changes in retinal tissues were observed using hematoxylin-eosin (HE) staining, and the number of corneal nerve fibers was observed under a microscope. The expressions of vascular endothelial growth factor (VEGF) and NDRG2/IL-6/STAT3 pathway genes in tissues were determined via quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR). Furthermore, the expressions of NDRG2/IL-6/STAT3 pathway proteins were determined via Western blotting.RESULTSThe level of blood glucose in model group was significantly higher than that of control group (p<0.05), suggesting successful modeling. The levels of tumor necrosis factor-α (TNF-α), IL-6, and IL-1 in model group were significantly higher than those of control group (p<0.05). The content of ROS and MDA in tissues was significantly higher in model group than the other two groups (p<0.05). However, SOD increased markedly in CLT-005 group and was close to that of control group. Besides, the number of corneal nerve fibers decreased remarkably in model group. However, it increased significantly in CLT-005 group, but was still smaller than that in control group. According to HE staining, there were significant retinal edema and telangiectasia in model group. Mild retinal edema and more ganglion cells and inner nuclear layers were observed in CLT-005 group than model group. QRT-PCR demonstrated that the mRNA expressions of VEGF, NDRG2, IL-6, and STAT3 were remarkably higher in model group than those in control group (p<0.05). However, they decreased significantly in CLT-005 group (p<0.05). Model group exhibited remarkably higher protein expressions of NDRG2, IL-6, and STAT3 than control group (p<0.05). However, CLT-005 group had decreased protein expressions of these molecules (p<0.05), which were close to those in control group.CONCLUSIONSThe activation of NDRG2/IL-6/STAT3 signaling pathway is positively correlated with the occurrence and development of DR in rats. Therefore, inhibiting the activation of NDRG2/IL-6/STAT3 signaling pathway can affect oxidation and antioxidation, thereby exerting a protective effect against retinal injury in diabetes rats.

10 Apr 2017·Investigative Opthalmology & Visual ScienceQ2 · MEDICINE

Inhibition of Stat3 by a Small Molecule Inhibitor Slows Vision Loss in a Rat Model of Diabetic Retinopathy

Q2 · MEDICINE

ArticleOA

Author: Phelps, Eric ; Vanlandingham, Phillip A. ; Farjo, Krysten M. ; Ma, Jian-Xing ; Quiambao, Alexander B. ; Nuno, Didier J. ; Farjo, Rafal A. ; Wassel, Ronald A.

PurposeDiabetic retinopathy is a leading cause of vision loss. Previous studies have shown signaling pathways mediated by Stat3 (signal transducer and activator of transcription 3) play a primary role in diabetic retinopathy progression. This study tested CLT-005, a small molecule inhibitor of Stat3, for its dose-dependent therapeutic effects on vision loss in a rat model of diabetic retinopathy.MethodsBrown Norway rats were administered streptozotocin (STZ) to induce diabetes. CLT-005 was administered daily by oral gavage for 16 weeks at concentrations of 125, 250, or 500 mg/kg, respectively, beginning 4 days post streptozotocin administration. Systemic and ocular drug concentration was quantified with mass spectrometry. Visual function was monitored at 2-week intervals from 6 to 16 weeks using optokinetic tracking to measure visual acuity and contrast sensitivity. The presence and severity of cataracts was visually monitored and correlated to visual acuity. The transcription and translation of multiple angiogenic factors and inflammatory cytokines were measured by real-time polymerase chain reaction and Multiplex immunoassay.ResultsStreptozotocin-diabetic rats sustain progressive vision loss over 16 weeks, and this loss in visual function is rescued in a dose-dependent manner by CLT-005. This positive therapeutic effect correlates to the positive effects of CLT-005 on vascular leakage and the presence of inflammatory cytokines in the retina.ConclusionsThe present study indicates that Stat3 inhibition has strong therapeutic potential for the treatment of vision loss in diabetic retinopathy.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetic macular oedema	Discovery	US	Charlesson LLC	-

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