Effect of brimonidine on retinal and choroidal neovascularization in a mouse model of retinopathy of prematurity and laser-treated rats.

PURPOSE: To determine whether chronic treatment with brimonidine (BRI) attenuates retinal vascular leakage and neovascularization in neonatal mice after exposure to high oxygen in a mouse model of retinopathy of prematurity (ROP), and choroidal neovascularization (CNV) in rats after laser treatment. METHODS: Experimental CNV was induced by laser treatment in Brown Norway (BN) rats. BRI or vehicle (VEH) was administered by osmotic minipumps, and CNV formation was measured 11 days after laser treatment. Oxygen-induced retinopathy was generated in neonatal mice by exposure to 75% oxygen from postnatal day (P)7 to P12. BRI or VEH was administered by gavage, and vitreoretinal vascular endothelial growth factor (VEGF) concentrations and retinal vascular leakage, neovascularization, and vaso-obliteration were measured on P17. Experimental CNV was induced in rabbits by subretinal lipopolysaccharide/fibroblast growth factor-2 injection. RESULTS: Systemic BRI treatment significantly attenuated laser-induced CNV formation in BN rats when initiated 3 days before or within 1 hour after laser treatment. BRI treatment initiated during exposure to high oxygen significantly attenuated vitreoretinal VEGF concentrations, retinal vascular leakage, and retinal neovascularization in P17 mice subjected to oxygen-induced retinopathy. Intravitreal treatment with BRI had no effect on CNV formation in a rabbit model of nonischemic angiogenesis. CONCLUSIONS: BRI treatment significantly attenuated vitreoretinal VEGF concentrations, retinal vascular leakage, and retinal and choroidal neovascularization in animal models of ROP and CNV. BRI may inhibit underlying event(s) of ischemia responsible for upregulation of vitreoretinal VEGF and thus reduce vascular leakage and retinal-choroidal neovascularization.

Inhibition of vitreoretinal VEGF elevation and blood-retinal barrier breakdown in streptozotocin-induced diabetic rats by brimonidine.

PURPOSE: To determine whether long-term brimonidine (BRI) treatment prevents the hyperglycemia-induced increase in vitreoretinal vascular endothelial growth factor (VEGF) expression and breakdown of the blood-retinal barrier (BRB) in streptozotocin (STZ)-induced diabetic rats. METHODS: Brown Norway/Long-Evans rats were divided into three groups with similar distributions of blood glucose and body weight. Two groups received a single intravenous injection of STZ (65 mg/kg) and the remaining control group received vehicle. Drug treatment administered via miniosmotic pumps was initiated 1 or 6 weeks later. The STZ-induced diabetic rats were treated with BRI (1 mg/kg/d) or vehicle (VEH) and control nondiabetic rats were treated with VEH for 4 weeks. Vitreoretinal VEGF protein, vitreal glutamate, and BRB breakdown were then measured. RESULTS: At 5 weeks after STZ treatment, STZ-treated diabetic rats demonstrated significantly elevated vitreoretinal VEGF expression, vitreal glutamate concentrations, and BRB leakage compared with nondiabetic control rats. Chronic BRI treatment had no effect on vitreal glutamate concentrations in diabetic animals but significantly decreased vitreoretinal VEGF expression and BRB breakdown to levels similar to those observed in control rats. BRI also significantly reduced BRB breakdown in aged diabetic rats at 10 weeks after STZ treatment. CONCLUSIONS: BRI produced marked decreases in vitreoretinal VEGF and inhibition of BRB breakdown in diabetic rats. The mechanism for these effects may involve attenuation of retinal NMDA receptor activity by BRI. The results suggest that BRI would be useful for treatment of ocular diseases associated with BRB leakage, such as diabetic macular edema and retinopathy.

Effect of memantine on neuroretinal function and retinal vascular changes of streptozotocin-induced diabetic rats.

PURPOSE: To test whether chronic memantine (MEM) treatment improves retinal function and prevents neurodegeneration and vascular changes in the retinas of streptozotocin (STZ)-induced diabetic rats. METHODS: Based on basal body weight and blood glucose, Brown Norway (BN) rats were divided into three groups. One group of rats was treated with vehicle (VEH), and the other two groups were treated with 65 mg/kg STZ. After 7 days, VEH-treated rats were treated further with a second VEH, and STZ-treated diabetic rats were treated either with the second VEH or with MEM (10 mg/kg daily) for another 3 to 4 weeks using mini-osmotic pumps. At end of the study, electroretinogram findings, retinal ganglion cell (RGC) count, vitreoretinal vascular endothelial growth factor (VEGF) protein levels, and blood-retinal barrier (BRB) breakdown of the animals were measured. RESULTS: Within 4 to 5 weeks of STZ treatment, the diabetic rats demonstrated significantly less retinal function and fewer RGCs than VEH-treated nondiabetic rats. The diabetic animals also had significantly elevated VEGF protein levels in retina and vitreous fluid and BRB breakdown compared with control nondiabetic rats. Chronic MEM treatment significantly improved retinal function and protected RGC loss in STZ-induced diabetic rats. MEM treatment also significantly decreased elevated vitreoretinal VEGF protein levels and retinal BRB leakage in the diabetic rats. This effect of MEM was not seen in nondiabetic rats. CONCLUSIONS: These results indicate that MEM could be useful for the treatment of ocular diseases, including diabetic retinopathy with neurodegeneration, elevated vitreoretinal VEGF protein levels, and increased BRB breakdown. In addition to the neuroprotective effect of this compound, MEM can reduce vascular changes seen in diabetic retinas. These data are the first to identify the vasculoprotective effect of MEM.

Unrestricted lineage differentiation of parthenogenetic ES cells.

The developmental potential of parthenogenetic embryonic stem (P-ES) cells was studied in teratomas and mouse chimaeras. Teratomas derived from P-ES cells contained a mixture of tissue types with variable proportions of specific tissues. Three of the eight P-ES cell lines analysed showed high proportions of striated muscle in teratomas, similar to teratomas from normal embryos or ES cell lines derived from fertilised embryos (F-ES cells). Our study also revealed that one P-ES cell line showed little lineage restriction in injection chimaeras. Descendants of the P-ES cells contributed to most tissues of chimaeric fetuses in patterns similar to F-ES cells. Normal colonisation of muscle, liver and pancreas was found in adult chimaeras. P-ES cells also showed similar haematopoietic differentiation and maturation as F-ES cells. However, extensive P-ES cell contribution was associated with a reduction in body size. These findings suggest that, while P-ES cells display more extensive developmental potential than the cells of parthenogenetic embryos from which they were derived, they only retained properties related to the presence of the maternal genome. To elucidate the molecular basis for the lack of lineage restriction during in vivo differentiation, the expression of four imprinted genes, H19, Igf2r, Igf2 and Snrpn was compared among five P-ES and two F-ES cell lines. Expression levels of these genes varied among the different ES cell lines, both in undifferentiated ES cells and in embryoid bodies.