FTY720 Attenuates Retinal Inflammation and Protects Blood–Retinal Barrier in Diabetic Rats

Abstract

Citation: Fan L, Yan H. FTY720 attenuates retinal inflammation and protects blood-retinal barrier in diabetic rats. Invest Ophthalmol Vis Sci. 2016;57:125457: -126357: . DOI:10.1167 PURPOSE. FTY720 has shown a protective effect in several diseases via inhibiting inflammation and decreasing vascular permeability. The purpose of this study was to assess the impact of FTY720 on inflammation and the blood-retinal barrier (BRB) in diabetic rats.METHODS. Male Wister rats were induced to develop diabetes by streptozotocin, and FTY720 was administered by oral gavage daily for 12 weeks. All experiments were performed at 12 weeks after model establishment. Gene expression was assessed by real-time PCR. Protein expression and/or distribution were assessed by Western blotting and/or immunohistochemistry. The BRB breakdown was determined by staining of retinal whole mounts and quantified using Evans blue.RESULTS. FTY720 induced lymphopenia in diabetic rats. Proinflammatory cytokines (TNF-a, IL-6, and IL-1b) and adhesion molecules (inter-cellular cell adhesion molecule-1 and vascular cell adhesion molecule-1) were increased in retinas of diabetic rats. FTY720 significantly inhibited the up-regulation of these inflammatory factors. FTY720 also suppressed nuclear factor-jB activation seen in retinas of diabetic rats. Additionally, FTY720 prevented BRB breakdown and reduction of tight junction proteins (ZO-1, Occludin, and Claudin-5) in the retinas of diabetic rats. Down-regulation of S1P1 and S1P3 was also reversed by FTY720 in retinas of diabetic rats.CONCLUSIONS. FTY720 provides protection against diabetic retinopathy (DR), which may involve its anti-inflammatory and barrier-enhancing effects. The S1PR modulation may serve as a novel approach to treat patients with DR.

Fingolimod Associated Bilateral Cystoid Macular Edema—Wait and See?

“…Owing to the fact that continuous treatment with fingolimod decreases surface expression of the S1P 1 receptor and that S1P 2 /S1P 3 activation increases endothelial barrier permeability [62], one possible explanation for the development of ME might be a shift of the balance from S1P 1 towards S1P 2 /S1P 3 signaling resulting in the activation of Rho/ROCK signaling pathways [62]. However, in one recent study, attenuation of retinal vascular leakages after a 12-week fingolimod treatment in streptozotocin (STZ)-induced diabetic rats has been reported [63]. Moreover, there are several works underlining that long-term treatment with fingolimod does not impair endothelial barrier function [64,65], which might be explained by the fact that, despite membrane downregulation, the internalized S1P 1 receptor still actuates signaling pathways [66] or that this function does not depend on the S1P 1 receptor at all [67].…”

Role of advanced glycation end products and sorbitol dehydrogenase in the pathogenesis of diabetic retinopathy

“…These results agreed with many studies (Giurdanella et al 2017) (Saker et al 2014), who postulated that AGE were localized to retinal blood vessels in diabetics and were correlated with the degree and clinical progression of retinopathy. (Giurdanella et al 2017) and (Saker et al 2014) found that AGE were elevated in various ocular tissues of diabetic subjects compared to diabetics without retinopathy (Navaratna et al 2007) (Fan and Yan 2016).This includes vitreous collagen (Fan and Yan 2016), where the AGE levels correlate with diabetic retinopathy (Kim et al There was no significant difference in the genotype distribution (C/C, C/G, G/G) of the C˗1214G polymorphism between the two groups of patients with and without DR. Also, there was no significant difference of G and C allele frequencies Fig. 1 Genotypes of the C/G polymorphism at the -1214-bp SDH promoter region determined by allele-specific PCR detection (ASO-PCR) and analyzed by 2% agarose gel electrophoresis, stained with ethidium bromide, and viewed under gel documentation system.…”

Involvement of Advanced Glycation End Products in the Pathogenesis of Diabetic Retinopathy

“…Adherens junctions (AJ) are mediated by VE-cadherin which promotes Ca 2+ -dependent homophilic cell to cell contacts, and interact intracellularly with actin cytoskeleton through catenins [36], while AGEs stimulation resulted in cleavage of VE-cadherin from the cell surface [39]. Treatments regarding to restore the expression of junction proteins are able to protect RECs from hyperglycemic insult to maintain their barrier properties [38,40]. Signaling events downstream of the AGE-RAGE pathway that dysregulate the junctional molecules were demonstrated in the last few years but still remained to be determined.…”

“…This conception was supported by the clinical results from Hoorn Study, a population-based cohort study, which recruited 625 patients and suggested that the prevalence of retinopathy was positively associated with tertiles of C reactive protein (CRP) and soluble intercellular cell adhesion molecule 1 (sICAM-1) [46]. Furthermore, it has been recognized that hyperglycemia deteriorates vasculature via inducing endothelial activation and proinflammatory phenotype of endothelial cells, which is marked by upregulation of cell surface adhesion molecules such as ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) [40].…”

“…With repeated aggressions, the ECs dropout and a platelet/fibrin thrombus is formed. Eventually, so does pericytes also disappear, resulting in capillary degeneration and occlusion [18,40,49]. The vascular inflammation also promotes generation of VEGF which therefore increases vascular permeability and later progresses angiogenesis [49].…”