dinoprost and Diabetic-Retinopathy

Diabetic retinopathy (DR) is the most frequent microvascular complications of diabetes and the leading cause of blindness in adults worldwide. Non-proliferative DR (NPDR) is the first stage of DR but currently has few recommended intervention. Eicosanoids play important roles in maintaining vessel homeostasis. However, the functions of eicosanoids in NPDR are still unknown. In this study, we investigated the eicosanoids profile difference in plasma between type 2 diabetes with NPDR or not. A total of 50 patients with type 2 diabetes were recruited and divided into non-DR (NDR) group and NPDR group based on fundus photographs. The eicosanoids profiles in plasma were determined by LC-MS/MS. Adhesion and transwell assay were used to detect the adhesion and migration effects of metabolites on primary bovine retinal pericyte cells (BRPC), respectively. Streptomycin (STZ)-induced diabetic mouse model was used to test the protective effects of selected metabolites according to retinal immunofluorescence staining and fluorescence confocal microscopy. Prostaglandin 2α (PGF2α) was decreased significantly in NPDR group compared to NDR group and negatively correlated with NPDR. In vitro, PGF2α was found to accelerate adhesion and migration by activating prostaglandin F receptor (FP receptor) and subsequent increasing RhoA activity in primary bovine retinal pericyte. Administration of PGF2α analogue diminished the damage on retinal capillary in an STZ-induced diabetic mouse model. Our results suggested that PGF2α may be a protective factor in the progression of NPDR in T2D patients. The protective mechanism of PGF2α was to increase pericyte mobility through FP receptor/RhoA pathway.

Topics: Animals; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Dinoprost; Disease Progression; Eicosanoids; Female; Humans; Male; Metabolome; Mice; Middle Aged

The aim of this study is to investigate markers of inflammation and oxidative stress in an early model of diabetic retinopathy, correlate retinal and plasma results and evaluate the influence of treatment by N-acetylcysteine (NAC), a free radical scavenger.. Four groups were studied: control (C), streptozotocin (STZ)-induced diabetic rats (D), STZ rats following 8 weeks of NAC (DT), and control rats following 8 weeks of NAC (CT). Plasma levels of free 15-F2t-isoprostane (15-F-2t-IsoP), superoxide dismutase (SOD) and tumour necrosis factor-alpha (TNF-alpha) were obtained. Primary antibodies against macrophages (ED-1), microglia (Ox-42), pericytes (NG-2), endothelial and perivascular cells (IB-4), haem oxygenase 1 (HO-1) and vascular endothelial growth factor (VEGF) were used.. Expression of NG-2 was robust in C, CT, DT, and mild in D. The intensity of IB-4 was higher in D and DT compared with the C and CT. Ox-42 and ED-1 expression was higher in the D than in the DT, C or CT. Expression of VEGF and HO-1 was non-specific across the four groups. Plasma levels of 15-F-2t-IsoP and TNF-alpha were higher in the D as compared with the C, CT and DT. SOD levels were lower in the D when compared with the C, CT and D.. Macrophage/microglia activation, pericyte loss and endothelial/perivascular cell changes occur early in the pathogenesis of DR. These changes are associated with an increase in plasma markers of oxidative stress and inflammation and are minimized by treatment with NAC. The results suggest that therapies that reduce free radicals will help minimize the early events in diabetic retinopathy in the STZ model.

Topics: Acetylcysteine; Animals; Biomarkers; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Dinoprost; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Free Radical Scavengers; Immunoenzyme Techniques; Inflammation; Isoprostanes; Macrophages; Male; Microglia; Oxidative Stress; Pericytes; Rats; Rats, Wistar; Retina; Superoxide Dismutase; Tumor Necrosis Factor-alpha

To determine the association of prostaglandins E1 (PGE1), E2 (PGE2), and F2-alpha (PGF2-alpha) with proliferative diabetic retinopathy (PDR) in human vitreous.. We collected human vitreous samples from eyes undergoing pars plana vitrectomy for proliferative diabetic retinopathy with vitreous hemorrhage (N=13) and for other reasons including macular gliosis and Stage IV idiopathic macular holes (N=7). Vitreal prostaglandins E1, E2, and F2-alpha were measured by radioimmunoassay.. Eyes with PDR had significantly lower vitreal levels of PGE1 (74.77 pg/ml +/- 15.70) compared to those without PDR (91.86 pg/ml +/- 13.36) (p=0.025) using t-test analysis. Eyes with PDR also had significantly lower levels of PGE2 (127.52 pg/ml +/- 70.52) compared to those eyes without PDR (194.43 pg/ml +/- 57.10) (p=0.045). In addition, eyes with PDR had significantly lower levels of PGF2-alpha (34.62 pg/ml +/- 11.56) compared to those eyes without PDR (51.43 pg/ml +/- 18.44) (p=0.021). Panretinal photocoagulation in diabetic eyes did not have an effect on vitreal concentrations of PGE1 (p=0.588). PGE2 (p=0.460) and PGF2-alpha (p=0.351), but sample size was too small.. Diabetic eyes with PDR had significantly lower vitreal levels of PGE1, PGE2 and PGF2-alpha compared to controls consistent with decreased production of these prostaglandins by the endothelial cells of diabetic eyes. Laser treatment did not appear to have a significant effect on vitreal concentrations of these prostaglandins, but sample size was small. The lower concentration of these vasodilatory prostaglandins may reflect the vasculature's inability to produce these substances and the vasoconstrictive state of the end-stage diabetic eye with PDR.

Topics: Aged; Alprostadil; Diabetic Retinopathy; Dinoprost; Dinoprostone; Female; Humans; Laser Coagulation; Male; Middle Aged; Radioimmunoassay; Vitrectomy; Vitreous Body; Vitreous Hemorrhage

Retinal hemodynamic responses to a F2-isoprostane, 8-epi-PGF2alpha, were quantitated in vivo in non-diabetic and diabetic rats using a video fluorescein angiography system. Vascular diameters and retinal mean circulation time were determined before and after 5 microl intra-vitreous injection of 8-epi-PGF2alpha (10(-5) to 10(-3) M), 10(-4) M 8-epi-PGF2alpha, + 10(-3) M SQ29,548 or 10(-3) M LCB2853 (two inhibitors of TXA2 receptor), 10(4) M 9beta-PGF2alpha, or the carrier in non-diabetic animals. Diabetic rats received either 8-epi-PGF2alpha 10(-4) M, or the carrier. Compared to control animals, diabetic rats presented in the basal state a venous vasodilation (P<0.01), without modification of retinal mean circulation time or blood flow. After intravitreous injection of 8-epi-PGF2alpha, a significant arterial vasoconstriction was observed in control but not in diabetic animals. This vasoconstriction was concomitant with increased retinal mean circulation time in control but not in diabetic rats, inducing an impaired reduction of blood flow. No vasoconstriction was observed after injection of either the carrier, 9beta-PGF2alpha or the isoprostane associated to the inhibitors of TXA2 receptors. This is the first direct observation that the isoprostane 8-iso-PGF2alpha is a potent vasoconstricting agent in the retina. It occurs at the arterial but not venous level, and is likely mediated through a TXA2-like receptor. Differences observed between control and diabetic animals suggest altered adaptative mechanisms toward vasoconstrictor substances (such as isoprostanes) in diabetic rats.

Topics: Angiography; Animals; Blood Flow Velocity; Bridged Bicyclo Compounds, Heterocyclic; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Dinoprost; Dose-Response Relationship, Drug; Fatty Acids, Unsaturated; Hydrazines; Male; Phenylacetates; Prostaglandin H2; Prostaglandins H; Rats; Rats, Wistar; Regional Blood Flow; Retinal Vessels; Sulfonamides; Vasoconstrictor Agents

The effect of 4 weeks streptozotocin-induced diabetes on ocular vascular resistance responses to noradrenalin (NA), adrenalin (A), phenylephrine (PHE), isoproterenol (ISOP), prostaglandin F2 alpha (PGF2 alpha). 5-hydroxytryptamine (5-HT) and angiotensin II (ANG II), was determined using a newly-developed, isolated, arterially-perfused rat eye preparation, by comparing responses from control and diabetic eyes. After extensive preliminary experiments to establish optimum parameters, the ophthalmic artery of enucleated control and diabetic rat eyes was cannulated and the retinal and uveal vasculature perfused at a constant flow with Na(+)-Krebs solution after streptozotocin-induced diabetes had been established for 4 weeks. The eyes were maintained in an environment-controlled organ bath. Perfusion pressure was monitored as increasing log M concentrations of agonists were added to the perfusate. Total ocular resistance could be calculated from knowledge of flow and pressure. In control eyes, NA, A, PHE, PGF2 alpha, and 5-HT all produced dose-dependent increases in total vascular resistance, with the following order of potency: NA = A > 5-HT > PHE = PGF2 alpha at 10(-4) M. The ocular circulation was not sensitive to isoproterenol and angiotensin II. In diabetic eyes responses to NA, A, PGF2 alpha and 5-HT were altered. Diabetic responses to NA and A had lower thresholds with larger resistance increases at low concentrations. However, the rate of increase in resistance with concentration was more gradual in diabetic eyes so that at 10(-4) M control responses were larger. Diabetic resistance responses to PGF2 alpha had the same threshold as in control eyes, but were greater in magnitude with an earlier peak at 10(-4) M. In contrast diabetic resistance responses to 5-HT were reduced, peaked at a lower resistance at 10(-4) M, but had the same threshold as those in the control eye. Basal vascular resistances in control: 3.14 +/- 0.32 mmHg min microliter-1 (n = 28), and diabetic eyes: 3.44 +/- 0.19, mmHg min microliter-1 (n = 36), were not significantly different. Vasoactivity in the early diabetic eye is disturbed with the effective balance between different agonists altered in favour of catecholamines at physiological concentrations. This may be related to the early changes in blood flow and oxygen distribution already reported in the rat eye, as well as changes to autonomic function. The isolated perfused rat eye is a valuable technique for investigating such va

Topics: Angiotensin II; Animals; Catecholamines; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Dinoprost; Eye; Isoproterenol; Male; Optic Nerve; Phenylephrine; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Serotonin; Vascular Resistance; Vasoconstrictor Agents