IκB Kinase-β Inhibitor IMD-0354 Beneficially Suppresses Retinal Vascular Permeability in Streptozotocin-Induced Diabetic Mice

Abstract

The purpose of the present study is to evaluate the effect of selective IKK-β inhibition by IMD-0354 on inflammation, apoptosis, and angiogenesis in diabetic retinopathy (DR). Six weeks after administration of a streptozotocin (STZ) injection, before diabetic retinopathy (DR) was evident, one group of STZ-induced diabetic mice was systemically administered with IMD-0354 (30 mg/kg) daily for another 6 weeks. Ten weeks after the STZ injection, with DR already present, another group of STZ-induced diabetic mice was administered IMD-0354 for 2 weeks. As controls, nondiabetic mice of the same age were treated with IMD-0354 for 6 weeks, and diabetic mice were treated with 10 μL of dimethyl sulfoxide (DMSO) for 6 weeks. Using these groups of mice, the following effects of IMD-0354 were analyzed: (1) inhibition of nuclear factor-κB (NF-κB) activation, (2) retinal morphology, (3) apoptotic signaling by cleaved caspase-3, (4) retinal vascular permeability, (5) angiogenesis of the retina, and (6) retinal production of VEGF. Systemic administration of IMD-0354 for 6 weeks to week-6 diabetic mice caused significant reduction in the loss of retinal ganglion cells and apoptotic signaling, with preservation of retinal vascular integrity and suppression of retinal VEGF expression. When inhibition of NF-κB activation treatment started after the onset of STZ-induced DR (week 10), IMD-0354 was still effective in preventing further DR progression while the vascular integrity was preserved. The present data indicate that NF-κB activation is the key step in the development of DR. Its suppression by IMD-0354 may present a promising therapeutic strategy for DR, especially in the early stages of the disease.