Duloxetine protects against experimental diabetic retinopathy in mice through retinal GFAP downregulation and modulation of neurotrophic factors. (September 2019)

• Record Type: Journal Article
• Authors: Bahr, Hoda I.; Abdelghany, Ahmed A.; Galhom, Rania A.; Barakat, Bassant M.; Arafa, El-Shaimaa A.; Fawzy, Manal S.
• Is Part Of: Experimental eye research. Volume 186(2019)
• Publication Date: 2019-09
• Subjects: Diabetic retinopathy -- Duloxetine -- GFAP -- GLUT-1 -- iNOS -- VEGF -- Neurotrophic factors -- Oxidative markers; ANOVA Analysis of variance -- DLX Duloxetine -- DR Diabetic retinopathy -- FDA Food and Drug Administration -- GAPDH Glyceraldehyde-3-phosphate dehydrogenase -- GCL Ganglionic cell layer -- GFAP Glial fibrillary acidic protein -- GLUT-1 Glucose transporter-1 -- GSH Reduced glutathione -- HRP Horseradish peroxidase -- INL Inner nuclear layer -- iNOS Inducible nitric oxide synthase -- IPL Inner plexiform layer -- MDA Malondialdehyde -- MIQE Minimum information for publication of quantitative real-time PCR experiments -- NGF Nerve growth factor -- OLM Outer limiting membrane -- ONL Outer nuclear layer -- PCR Polymerase chain reaction -- PR Photo receptors layer -- PVDF Polyvinylidene difluoride -- qPCR Quantitative polymerase Chain Reaction RGC Retinal ganglion cell -- RNA Ribonucleic acid -- RPE Retinal pigment epithelium -- RT Reverse transcription -- SD Standard deviation -- SNRI Selective serotonin and norepinephrine reuptake inhibitor -- TBST Tris buffered saline with Tween 20 -- TGF-β Transforming growth factor beta -- VEGF Vascular endothelial growth factor; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2019.107742
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: Diabetic retinopathy (DR) is recognized as one of the leading causes of blindness worldwide. Searching and validation for a novel therapeutic strategy to prevent its progress are promising. This work aimed to assess the retinal protective effects of duloxetine (DLX) in Alloxan-induced diabetic mice model. Animals were equally and randomly divided to four groups (eight mice per group); group 1: is the control group, 2: diabetic group, 3&4: diabetic and after 9 weeks received DLX for 4 weeks (15 mg/kg and 30 mg/kg), respectively. Quantitative real-time PCR (qPCR) analysis revealed nerve growth factor ( NGF ), inducible nitric oxide synthase ( iNOS ) and transforming growth factor beta ( TGF-β ) genes upregulation in the diabetic group compared to controls. Also, increased retinal malondialdehyde (MDA) and the decline of reduced glutathione (GSH) levels were observed. The morphometric analysis of diabetic retina revealed a significant reduction in total retinal thickness compared to control. Diabetic retinal immunostaining and Western blot analyses displayed glial fibrillary acidic protein (GFAP) and vascular endothelial cell growth factor (VEGF) proteins expression upregulation as well as glucose transporter-1 (GLUT-1) downregulation comparing to controls. However, DLX-treated groups showed downregulated NGF, iNOS, and TGF-β that was more obviously seen in the DLX-30 mg/kg group than DLX-15 mg/kg group. Furthermore, these groups showed amelioration of the oxidative markers; MDA and GSH, retaining the total retinal thickness nearly to control, GFAP and VEGF downregulation, and GLUT-1 upregulation compared to diabetic group. Taken together, it could be summarized that duloxetine can attenuate DR via the anti-inflammatory and the anti-oxidative properties as well as modulating the angiogenic and the neurotrophic factors expressions. This could hopefully pave the road to be included in the novel list of the therapeutic regimen for DR after validation in the clinic. Graphical abstract: Image 1 Highlights: NGF, iNOS and TGF-β genes over-expression was observed in diabetic mice. Diabetic retinal immunostaining displayed GFAP upregulation and GLUT-1 protein expression downregulation. Increased malondialdehyde (MDA) levels and decline of reduced glutathione (GSH) levels were observed in diabetic retinae. Western blot analysis of diabetic retina displayed upregulation of GFAP and VEGF, and downregulation of GLUT-1 expression. Duloxetine can attenuate DR via the anti-inflammatory/anti-oxidative properties, and the neurotrophic factors modulation.