pyrimidinones and Diabetic-Retinopathy

Oxidative stress and blood-retinal barrier (BRB) damage induced by hyperglycemia are the principal processes involved in the early stages of diabetic retinopathy (DR). CXC chemokine receptor 3 (CXCR3)-mediated inflammatory infiltration exists in many disease models. The main objective of the present study was to determine whether AMG487, a CXCR3 antagonist, can ameliorate BRB disruption and reactive oxygen species generation in the DR model. The retinal endothelial cell and ganglion cell ultrastructures were observed using a transmission electron microscope. The pericyte marker PDGFR-β, tight junction occludin, and leaking albumin were evaluated. The oxidative stress level, CCAAT-enhancer-binding protein homologous protein (CHOP), and p-p38 expression were also investigated in vivo and in vitro. The results indicated that AMG487 application might alleviate PDGFR-β and occludin loss, and decreased the residual content of retinal albumin in the streptozocin-induced DR mouse model via the inhibition of oxidative and endoplasmic reticulum stress, in which p38 activation was also involved. Thus, CXCR3 inhibition might be a target to prevent the early stage of DR injury.

Topics: Acetamides; Animals; Antioxidants; Blood-Retinal Barrier; Diabetic Retinopathy; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Pyrimidinones; Reactive Oxygen Species; Receptors, CXCR3

Lipoprotein-associated phospholipase A2 (Lp-PLA2) hydrolyses oxidized low-density lipoproteins into proinflammatory products, which can have detrimental effects on vascular function. As a specific inhibitor of Lp-PLA2, darapladib has been shown to be protective against atherogenesis and vascular leakage in diabetic and hypercholesterolemic animal models. This study has investigated whether Lp-PLA2 and its major enzymatic product, lysophosphatidylcholine (LPC), are involved in blood-retinal barrier (BRB) damage during diabetic retinopathy. We assessed BRB protection in diabetic rats through use of species-specific analogs of darapladib. Systemic Lp-PLA2 inhibition using SB-435495 at 10 mg/kg (i.p.) effectively suppressed BRB breakdown in streptozotocin-diabetic Brown Norway rats. This inhibitory effect was comparable to intravitreal VEGF neutralization, and the protection against BRB dysfunction was additive when both targets were inhibited simultaneously. Mechanistic studies in primary brain and retinal microvascular endothelial cells, as well as occluded rat pial microvessels, showed that luminal but not abluminal LPC potently induced permeability, and that this required signaling by the VEGF receptor 2 (VEGFR2). Taken together, this study demonstrates that Lp-PLA2 inhibition can effectively prevent diabetes-mediated BRB dysfunction and that LPC impacts on the retinal vascular endothelium to induce vasopermeability via VEGFR2. Thus, Lp-PLA2 may be a useful therapeutic target for patients with diabetic macular edema (DME), perhaps in combination with currently administered anti-VEGF agents.

Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Animals; Biphenyl Compounds; Blood-Retinal Barrier; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Male; Permeability; Pyrimidinones; Rabbits; Rats, Inbred BN; Vascular Endothelial Growth Factor A