Inhibition of NF-κB ameliorates aberrant retinal glia activation and inflammatory responses in streptozotocin-induced diabetic rats

Abstract

Background To determine the anti-inflammatory effects of IMD-0354, a specific NF-κB blocker, on glial cells in rats with streptozotocin (STZ)-induced diabetic retinopathy (DR). Methods The following four groups of rats were used: control, control + IMD-0354, STZ, and STZ + IMD-0354. After six weeks of STZ injection, diabetic rats and nondiabetic control rats received IMD-0354 (30 mg/kg) or an equal volume of 4% dimethyl sulfoxide (DMSO) in phosphate-buffered saline intraperitoneally for six consecutive weeks. The following four groups of primary rat retinal microglia and Müller cells were used: control (5 mM), control + IMD-0354, high glucose (20 mM), and high glucose + IMD-0354. The effects of IMD-0354 on nuclear factor-κB (NF-κB) activation, oxidative stress strength, expression of inflammatory cytokines and VEGF (vascular endothelial growth factor), activation of glial cells, and apoptosis of neuron cells were evaluated by immunohistochemistry, oxidative stress assays, western blot, enzyme linked immunosorbent assay (ELISA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining respectively. Results Nuclear translocation of NF-κB was markedly increased in diabetic rat retina and high glucose treated glial cells. Systemic administration of IMD-0354 significantly inhibited NF-κB activation in both diabetic rat retina and high glucose treated glial cells, ameliorated oxidative injury, inflammatory responses, VEGF production and glial cell activation, and protected neurons from apoptosis. Conclusions Our findings indicated that NF-κB activation is acritical step in the abnormal reactivity of glial cells in STZ-induced diabetic rats. Inhibition effect of IMD-0354 on NF-κB activation may represent a promising therapeutic strategy for DR via a variety of mechanisms, including inflammation reduction and glial cells regulation.

Complementary Approaches to Retinal Health Focusing on Diabetic Retinopathy

“…They examined the effectiveness of an intraperitoneal injection of an IKKβ inhibitor (IMD-0354), which reduced the expressions of NFκB, VEGF, inflammatory cytokines, and glial fibrillary acidic protein (GFAP); furthermore, the number of apoptotic cells also decreased in the retina. This treatment also caused the elevation of decreased antioxidants (superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH)-Px) levels in diabetic rat retinas [44]. In another rat DR model, the effectiveness of NFκB inhibitors was also described by reducing ganglion cell death and GFAP expression in N-methyl-D-aspartate (NMDA)-induced retinal excitotoxicity [45].…”

Nutraceuticals for Diabetic Retinopathy: Recent Advances and Novel Delivery Systems

“…Upregulation of pro-inflammatory chemokines such as interleukin (IL)-8, IL-1β, and tumor necrosis factor (TNF)-α have been detected in the aqueous and vitreous fluid as well as the serum of patients with PDR [ 16 , 17 , 18 , 19 ]. The pivotal mediators of inflammatory responses, nuclear factor-kappa B (NF-κB) and NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes are also highly related to the progression of DR [ 20 , 21 , 22 , 23 ]. Inflammation partly contributes to pericyte depletion and leukostasis, the adhesion of leukocytes to the retinal vasculature [ 24 ].…”

Diabetic Neuropathy of the Retina and Inflammation: Perspectives

“…Recent studies indicate that several anti-inflammatory therapies ameliorate the pathogenesis of diabetic retinopathy in diabetic models in vivo and in vitro, including IMD-0354, a specific NF-κB blocker [95], GSK-872, specific necroptosis inhibitor [96], hsa_circ_0000047 which targets miR-6720-5p/CYB5R2 axis [97], topical administrated NADPH oxidases 4 inhibitor, GLX7013114 [98], a non-steroid mineralocorticoid receptor, finerenone [99], and miRNA-124 [100]. Although there are a variety of diabetic models, including rodents and Drosophila, which are available worldwide, no ideal models of diabetic retinopathy have been established yet [101,102].…”