Extract of Polygonum cuspidatum Attenuates Diabetic Retinopathy by Inhibiting the High-Mobility Group Box-1 (HMGB1) Signaling Pathway in Streptozotocin-Induced Diabetic Rats

Abstract

High-mobility group box-1 (HMGB1) is a well-known pro-inflammatory cytokine. We aimed to investigate the effect of the ethanol extract of the root of P. cuspidatum (PCE) on retinal inflammation in diabetic retinopathy. PCE (100 or 350 mg/kg/day) was administered to diabetic rats for 16 weeks, and hyperglycemia and body weight loss developed in the diabetic rats. The retinal expression levels of HMGB1 and receptor for advanced glycation end products (RAGE) and the activity of nuclear factor-kappa B (NF-κB) in the retina were examined. Additionally, a chromatin immunoprecipitation assay was performed to analyze the binding of NF-κB binding to the RAGE promoter in the diabetic retinas. The levels of HMGB1 and RAGE expression, NF-κB activity, and NF-κB binding to the RAGE promoter were increased in the diabetic retinas. However, treatment with PCE ameliorated the increases in HMGB1 and RAGE expression, and NF-κB activity in the retina. In addition, in diabetic rats, retinal vascular permeability and the loosening of the tight junctions were inhibited by PCE. These findings suggest that PCE has a preventative effect against diabetes-induced vascular permeability by inhibiting HMGB1-RAGE-NF-κB activation in diabetic retinas. The oral administration of PCE may significantly help to suppress the development of diabetic retinopathy in patients with diabetes.

High Mobility Group Box-1 and Diabetes Mellitus Complications: State of the Art and Future Perspectives

“…Moreover, El-Asrar and coworkers demonstrated that levels of HMGB1 are higher in patients with PDR and retinal hemorrhages, suggesting a role of the protein in PDR progression [126]. The pro-inflammatory action of HMGB1 even in retinal cells is promoted by the linkage to TLR-4 [130,131] and RAGE [122,[131][132][133], and the activation of ERK1/2 and NF-kB signaling [132]. In fact, the intravitreal administration of the protein enhances these pathways and downregulates TLR-2 and occludin expression, enhancing retinal vasopermeability [134].…”

“…In particular, Mohammad and coworkers showed that HMGB1 induced NADPH-oxygen-derived ROS, causing retinal cells apoptosis [134]. They also showed that HMGB1 induced cleaved caspase-3, IL-1β and PARP-1, and that this effect is inhibited by administration of GA. Interestingly, in a work by Sohn and coworkers, the administration in diabetic rats of extract of Polygonum cuspidatum (PCE), a dried root with anti-inflammatory action, reduced HMGB1, RAGE and NF-kB expression and it ameliorated vascular retinal permeability, inhibiting tight junction leakage [133]. To support evidences of HMGB1 activity on progression of DR, Jiang and coworkers demonstrated that intravitreal injection of HMGB1 siRNA in rats reduced retinal damage and cellular death and it improved retinal function [135].…”

Dietary Compound Chrysin Inhibits Retinal Neovascularization with Abnormal Capillaries in db/db Mice

“…However, they have not been proven effective in randomized, controlled trials. Natural products may serve as specific, efficacious, and affordable agents for a potential DR therapy [26,27,28]. Epigallocatechin-3-gallate (EGCG) inhibits ocular neovascularization and vascular permeability via suppression of MMP-9 and VEGF activation [26].…”

Phytochemical Management of Diabetic Complications, Experimental Evidences

“…cuspidatum has been used clinically for the treatment of constipation, gallstones, hepatitis, and inflammation [62]. An investigation on the effect of the ethanol extract of the root of P. cuspidatum (PCE) on retinal inflammation in diabetic retinopathy suggests that PCE has a preventative effect against diabetes-induced vascular permeability by inhibiting high mobility group box-1-RAGE-NF-_B activation in diabetic retinas [63].…”