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Yuichiro Ogura

Publications and source records attributed to Yuichiro Ogura.

At least 19 recordsLinked to original sources
PubMed2006

Corneal avascularity is due to soluble VEGF receptor-1.

Corneal avascularity-the absence of blood vessels in the cornea-is required for optical clarity and optimal vision, and has led to the cornea being widely used for validating pro- and anti-angiogenic therapeutic strategies for many disorders. But the molecular underpinnings of the avascular phenotype have until now remained obscure and are all the more remarkable given the presence in the cornea of vascular endothelial growth factor (VEGF)-A, a potent stimulator of angiogenesis, and the proximity of the cornea to vascularized tissues. Here we show that the cornea expresses soluble VEGF receptor-1 (sVEGFR-1; also known as sflt-1) and that suppression of this endogenous VEGF-A trap by neutralizing antibodies, RNA interference or Cre-lox-mediated gene disruption abolishes corneal avascularity in mice. The spontaneously vascularized corneas of corn1 and Pax6+/- mice and Pax6+/- patients with aniridia are deficient in sflt-1, and recombinant sflt-1 administration restores corneal avascularity in corn1 and Pax6+/- mice. Manatees, the only known creatures uniformly to have vascularized corneas, do not express sflt-1, whereas the avascular corneas of dugongs, also members of the order Sirenia, elephants, the closest extant terrestrial phylogenetic relatives of manatees, and other marine mammals (dolphins and whales) contain sflt-1, indicating that it has a crucial, evolutionarily conserved role. The recognition that sflt-1 is essential for preserving the avascular ambit of the cornea can rationally guide its use as a platform for angiogenic modulators, supports its use in treating neovascular diseases, and might provide insight into the immunological privilege of the cornea.

Animals↗
PubMed2006

Loss of SPARC-mediated VEGFR-1 suppression after injury reveals a novel antiangiogenic activity of VEGF-A.

VEGF-A promotes angiogenesis in many tissues. Here we report that choroidal neovascularization (CNV) incited by injury was increased by excess VEGF-A before injury but was suppressed by VEGF-A after injury. This unorthodox antiangiogenic effect was mediated via VEGFR-1 activation and VEGFR-2 deactivation, the latter via Src homology domain 2-containing (SH2-containing) tyrosine phosphatase-1 (SHP-1). The VEGFR-1-specific ligand placental growth factor-1 (PlGF-1), but not VEGF-E, which selectively binds VEGFR-2, mimicked these responses. Excess VEGF-A increased CNV before injury because VEGFR-1 activation was silenced by secreted protein, acidic and rich in cysteine (SPARC). The transient decline of SPARC after injury revealed a temporal window in which VEGF-A signaling was routed principally through VEGFR-1. These observations indicate that therapeutic design of VEGF-A inhibition should include consideration of the level and activity of SPARC.

Angiogenesis Inhibitors↗
PubMed2006

Drug delivery from ocular implants.

Developing an intraocular drug delivery system (DDS) is urgently needed because most vitreoretinal diseases are refractory to conventional pharmacological approaches; eye drops and systemically administered drugs cannot deliver therapeutic drug concentrations into vitreoretinal tissue. Intraocular DDSs address this problem. Intraocular sustained-drug release via implantable devices or injectable microparticles has been investigated to treat vitreoretinal diseases. A nonbiodegradable implant was first used in 1996 for cytomegalovirus retinitis secondary to the acquired immunodeficiency syndrome. Biodegradable implants, composed of hydrophilic or hydrophobic polymers, in the shape of rods, plugs, discs or sheets have been investigated. An injectable rod is presently being assessed in a Phase III trial to treat macular oedema secondary to diabetic retinopathy or branch-retinal vein occlusion. Intraocular DDSs using a biodegradable implant may soon be successfully used to treat serious intraocular disorders.

Animals↗
PubMed2006

[Incidence and risk factors of intraocular pressure elevation after triamcinolone acetonide administration for macular disorders].

PURPOSE: We investigated the incidence and risk factors of intraocular pressure (IOP) elevation following triamcinolone administration for macular disorders. METHODS: Intravitreal or posterior sub-Tenon's injections of triamcinolone acetonide were conducted on 119 eyes with macular disorders. The change in IOP was followed for all cases. Risk factors for IOP elevation were examined regarding causal disease, history of vitrectomy, methods of injection, frequency of injection, refractive power, and age. RESULT: The difference between the mean baseline IOP (13.0 +/- 2.9 mmHg) and the maximum mean IOP (21.5 +/- 9.8 mmHg) was statistically significant (p< 0.0001). The final mean IOP was 15.1 +/- 3.6 mmHg. Forty-one eyes (34.5%) had IOP elevation over 21 mmHg during the follow-up. Fifty-nine eyes (49.6%) showed pressure elevation of over 5 mmHg. One eye (1%) required trabeculotomy to control the IOP. Risk factors for the IOP elevation included younger age, high myopia, no history of vitrectomy, and multiple injections. CONCLUSION: Careful follow-up of the IOP is required after triamcinolone acetonide injections.

Age Factors↗
PubMed2005

Intraocular sustained drug delivery using implantable polymeric devices.

Vitreoretinal diseases involving age-related macular degeneration (AMD) are refractory to most topical or systemic drugs. The retina and the vitreous cavity have a unique position regarding pharmacokinetics in that the inner and outer blood retinal barriers separate the retina and vitreous from the systemic circulation. Eye drops achieve minimal therapeutic concentrations in the vitreoretinal tissue. Drug delivery systems are a strategy to address this. Intraocular sustained drug release using implantable devices has been investigated to treat vitreoretinal diseases. Possible targeted diseases include those in which repeated intraocular injections are effective (cytomegalovirus retinitis, uveitis), diseases requiring surgery (proliferative vitreoretinopathy), and chronic diseases (AMD, macular edema, retinitis pigmentosa). Hydrophobic or hydrophilic polymers shaped into a sheet, disc, rod, plug, or a larger device can be implanted into the subretinal space, intrascleral space, vitreous space, peribulbar space, or at the pars plana. Many researchers suggest the feasibility of these implants to treat AMD.

Animals↗
PubMed2005

Protective effect of polyethylene glycol-superoxide dismutase on leukocyte dynamics in rat retinal microcirculation under lipid hydroperoxide-induced oxidative stress.

The levels of lipid hydroperoxide (LHPs) in vitreous are elevated in a variety of retinal disorders. Recently, we have shown that increased levels of LHPs in the vitreous enhanced leukocyte-endothelium interaction in the retina, which should contribute to the initial disturbance of the retinal microcirculation. Based upon the previous work, the purpose of the present study was to investigate the effect of polyethylene glycol-superoxide dismutase (PEG-SOD), one of the important enzyme antioxidants, on leukocyte-endothelial interaction in the retinal microcirculation under LHP-induced oxidative stress. Male Brown-Norway rats weighing approximately 250 g were used. LHP(18:2) was made from linoleic acid (LA) with lipoxygenase and 10 microg of LHP dissolved in 5 microl of sodium borate buffer (SBB, 0.02 m) was slowly injected into the vitreous using a 33-gauge needle. PEG-SOD (5000 units/kg) was given intravenously 5 min before LHP injection. At 2, 4, 6, 12, 24 and 48 hr after the vitreous injections, we evaluated the number of rolling leukocytes along the major retinal veins and the number of leukocytes that accumulated in the retinal microvasculature with acridine orange digital fluorography. In LHP-treated rats, leukocyte rolling along the major retinal veins was maximal at 6 hr after LHP injection. The number of rolling leukocytes in the PEG-SOD-treated rats was decreased to 5.5% of those in the LHP-treated rats at 6 hr after LHP injection (P<0.01). No rolling leukocytes were observed in either control or vehicle-treated eyes. The number of accumulated leukocytes in LHP-treated eyes started to increase at 12 hr, and peaked at 24 hr which was significantly higher than in both control and vehicle-treated eyes (P<0.01). The number of accumulated leukocytes in the PEG-SOD-treated rats was reduced by 88.0% at 24 hr (P<0.01). Intravenous injection of PEG-SOD significantly inhibited the leukocyte rolling and its accumulation under LHP-induced oxidative stress. These results suggest that PEG-SOD might attenuate various retinal microcirculatory disorders associated with LHP.

Animals↗
PubMed2005

Insulin enhances leukocyte-endothelial cell adhesion in the retinal microcirculation through surface expression of intercellular adhesion molecule-1.

The purpose of this study was to evaluate the effects of insulin on leukocyte-endothelial cell adhesion in the retinal microcirculation in vitro and in vivo. Human retinal endothelial cells (HRECs) were cultured in medium with or without insulin, and neutrophils allowed to adhere. Adherent neutrophils were quantified by measuring myeloperoxidase activity. Surface expression of endothelial adhesion molecules were studied with the use of an enzyme immunoassay. Insulin at concentrations of 50 and 100 microU/ml significantly increased neutrophil adhesion to HRECs compared with the control cells (P < 0.01, respectively). Surface expression of intercellular adhesion molecule-1 (ICAM-1) significantly increased when HRECs were exposed to 100 microU/ml insulin, as compared with the control cells (P < 0.05). Anti-ICAM-1 antibody significantly inhibited neutrophils adhesion to HRECs (P < 0.0001). Brown-Norway rats received subcutaneous injection of 0.2 U per 100 g body weight insulin three times. Control rats received the same amount of phosphate-buffered saline. Leukocyte entrapment in the retina was evaluated using acridine orange leukocyte fluorography. The number of leukocytes trapped in the retina of insulin-treated rats was significantly elevated compared with that in the control animals (P < 0.0001). These results suggested that insulin enhances leukostasis in retinal microcirculation. Hyperinsulinemia may be a risk factor of retinal microcirculatory disturbances.

Acridine Orange↗
PubMed2005

Suppression of laser-induced choroidal neovascularization by posterior sub-tenon administration of triamcinolone acetonide.

PURPOSE: To evaluate the inhibitory effect of triamcinolone acetonide (TA) on choroidal neovascularization (CNV) by posterior sub-Tenon administration using a laser-induced CNV model in the rat. METHODS: Experimental CNV was induced by laser photocoagulation in Brown-Norway male rats. Experimental eyes received posterior sub-Tenon administration of either 2 mg (n = 10) or 0.5 mg (n = 8) of TA. Control eyes (n = 10) received posterior sub-Tenon administration of isotonic sodium chloride solution. Two weeks after treatment, CNV was evaluated by fluorescein angiography and histopathological examination. Concentrations of TA in the vitreous, retina, and choroid were determined by high-performance liquid chromatography at 3 and 7 days after posterior sub-Tenon administration. RESULTS: The eyes treated with 2 mg of TA showed statistically significant inhibition of fluorescein leakage by fluorescein angiography, as compared with control eyes and eyes treated with 0.5 mg of TA (P < 0.01). The thickness of CNV membranes in eyes treated with 2 mg of TA also decreased statistically significantly, as compared with control eyes (P < 0.01). TA was detected in the vitreous, retina, and choroid 3 days after administration and in the choroid 7 days after administration. CONCLUSIONS: Posterior sub-Tenon administration of TA may be useful to treat CNV.

Animals↗
PubMed2005

Effect of benzalkonium chloride on transscleral drug delivery.

PURPOSE: To investigate the effect and safety of benzalkonium chloride on transscleral drug delivery in the rabbit after continuous intrascleral administration. METHODS: Betamethasone 21-phosphate (BP) aqueous solutions, with or without benzalkonium chloride (BAK), were continuously administered to albino rabbit sclera with an osmotic pump for 1 week. The BP concentrations in the aqueous humor, vitreous, and retina-choroid were measured by high-performance liquid chromatography (HPLC). To investigate the effect of BAK on scleral permeability of BP in vitro, penetration of BP aqueous solution with or without BAK across the rabbit sclera was evaluated using a two-chamber Ussing apparatus. To determine the effects of BAK on transscleral delivery of large molecules, 20- and 70-kDa fluorescein isothiocyanate (FITC)-dextran (FD-20 and -70, respectively) aqueous solutions, with or without BAK, were continuously administered to the sclera by an osmotic pump. The intensity of fluorescence in the aqueous humor, vitreous, and retina-choroid was measured by fluorescence spectrophotometry at 1 week after implantation of the pump. The retinal toxicity of BAK was evaluated electrophysiologically and histologically. RESULTS: BAK increased concentrations of BP in the vitreous and retina-choroid compared with the control. BP was not detected in the aqueous humor. In the in vitro study, BAK did not increase the scleral permeability of BP. In the retina-choroid, BAK significantly increased concentrations of FD-20 but did not increase those of FD-70. The addition of BAK did not increase concentrations of FD-20 or -70 in the vitreous. No substantial toxic reactions were observed in the retina in electrophysiological or histologic examinations after the addition of BAK. CONCLUSIONS: The results of this study demonstrate that BAK may improve the ocular penetration of a drug in a transscleral drug delivery system without producing toxic reactions.

Animals↗
PubMed2004

Drug delivery systems for vitreoretinal diseases.

The eye has an environment that is specific unto itself in terms of pharmacokinetics: the inner and outer blood-retinal barriers separate the retina and the vitreous from the systemic circulation and vitreous body, which physiologically has no cellular components, occupies the vitreous cavity, an inner space of the eye, and reduces practical convection of molecules. Considering this, development of a drug delivery system (DDS) is becoming increasingly important in the treatment of vitreoretinal diseases not only to facilitate drug efficacy but also to attenuate adverse effects. The DDS has three major goals: enhances drug permeation (e.g., iontophoresis and transscleral DDS), controls release of drugs (e.g., microspheres, liposomes, and intraocular implants), and targets drugs (e.g., prodrugs with high molecular weight and immunoconjugates). Comprehensive knowledge of these should lead to development of innovative treatment modalities.

Absorbable Implants↗
PubMed2004

Feasibility of drug delivery to the posterior pole of the rabbit eye with an episcleral implant.

PURPOSE: To evaluate the feasibility of a nonbiodegradable polymeric episcleral implant as a new controlled intraocular delivery system of betamethasone (BM) to the posterior pole of the eye. METHODS: The episcleral implant, which is composed of a drug-releasing component and a suture tag, released BM through an ethylene vinyl acetate membrane. The implants were placed on the sclera in 12 eyes of 12 Japanese white rabbits so that the drug-releasing surface could attach to the sclera at the posterior pole. BM concentrations in the aqueous humor, vitreous, and retina-choroid (posterior half and anterior half) were determined by high-performance liquid chromatography (HPLC) at weeks 1, 2, and 4 after implantation. In addition, the intraocular tissue distribution of the drug was evaluated by fluorescein microscopy after implantation of the implant loaded with 6-carboxy fluorescein diacetate (6-CFDA) as a drug marker. Retinal toxicity was evaluated by electroretinography and histologic examination. RESULTS: The implant showed zero-order release profiles both in vitro and in vivo for 4 weeks. BM concentrations in the retina-choroid after implantation were maintained above the concentrations effective for suppressing inflammatory reactions for at least 4 weeks. The BM concentration was greater in the posterior half of the retina-choroid than in the vitreous. It was confirmed that 6-CFDA penetrated through the sclera and dispersed into the retina-choroid. Fluorescence from 6-CFDA gradually decreased in intensity with increased distance from the implantation site. Electroretinography and histologic study showed no substantial toxic reactions. CONCLUSIONS: These findings suggest that the episcleral implant may be a useful drug carrier for intraocular delivery of BM, especially for the posterior part of the eye.

Animals↗
PubMed2004

Platelets adhering to the vascular wall mediate postischemic leukocyte-endothelial cell interactions in retinal microcirculation.

PURPOSE: Recent evidence suggests that platelets play a major role in ischemia-reperfusion injury, not only through thrombus formation but also through participation in inflammatory reactions with leukocytes. This study was designed to investigate the contribution of platelets in leukocyte recruitment to inflamed regions in vivo. METHODS: Thrombocytopenia was produced in male Long-Evans rats by intravenous injection of anti-platelet serum at 4 hours before ischemia-reperfusion. Leukocyte behavior in retinal microcirculation was evaluated with acridine orange digital fluorography. Expression of P-selectin in the postischemia retina was investigated by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. After 14 days of reperfusion, ischemia-induced retinal damage was evaluated histologically. RESULTS: Leukocyte rolling along major retinal veins of thrombocytopenic rats was dramatically suppressed, and subsequent leukocyte accumulation in the postischemia retina was also significantly reduced (72.3%; P < 0.001) at 24 hours after reperfusion. Although RT-PCR revealed no significant reduction of P-selectin mRNA in platelet-depleted rat retina after transient ischemia, immunohistologic examination showed suppression of P-selectin expression on the vascular wall. Another immunologic examination using anti-platelet antibody detected adherent platelets, which can also express P-selectin on their surfaces, on postischemic vascular endothelium in vehicle-treated retina. Moreover, blockage of platelet glycoprotein IIb/IIIa resulted in substantial inhibition of leukocyte rolling. In addition, histologic examination showed the participation of platelets in retinal ischemia-reperfusion injury. CONCLUSIONS: This study demonstrated that the expression of P-selectin on platelets may contribute to the recruitment of leukocytes to tissues after ischemia.

Acridine Orange↗
PubMed2004

[Significance of leukocytes in the regulation of retinal edema, ischemia, and angiogenesis].

BACKGROUND: Involvement of leukocytes in three major pathologic conditions in the retina, i.e., edema, ischemia, and angiogenesis, has recently been thoroughly investigated. The accumulated evidence will lead to an integrated understanding of the relationship between leukocytes and retinal disorders, which is required for clinical applications of new medical treatment. METHOD: Leukocyte roles in the retinal vascular pathology were assessed by reviewing the related literature. RESULTS: Vascular endothelial growth factor(VEGF)-induced leukocyte adhesion to the retinal vessels was shown to result in blood-retinal barrier breakdown, and the leukocyte-mediated pathogenesis was also seen in a model of diabetic retinopathy. A possible mechanism by which retinal angiogenesis develops intraviteral proliferation instead of compensating the avascular retina is that VEGF-producing monocytes/macrophages infiltrate the vitreous with subsequent migration of retinal vascular endothelial cells. On the other hand, cytotoxic T lymphocyte-mediated apoptosis of endothelial cells appears to cause the suppression of pathological retinal angiogenesis and the formation of ischemic retina secondary to vascular regression. CONCLUSION: Leukocytes are considered to regulate retinal edema, ischemia, and angiogenesis.

Animals↗
PubMed2003

VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization.

Hypoxia-induced VEGF governs both physiological retinal vascular development and pathological retinal neovascularization. In the current paper, the mechanisms of physiological and pathological neovascularization are compared and contrasted. During pathological neovascularization, both the absolute and relative expression levels for VEGF164 increased to a greater degree than during physiological neovascularization. Furthermore, extensive leukocyte adhesion was observed at the leading edge of pathological, but not physiological, neovascularization. When a VEGF164-specific neutralizing aptamer was administered, it potently suppressed the leukocyte adhesion and pathological neovascularization, whereas it had little or no effect on physiological neovascularization. In parallel experiments, genetically altered VEGF164-deficient (VEGF120/188) mice exhibited no difference in physiological neovascularization when compared with wild-type (VEGF+/+) controls. In contrast, administration of a VEGFR-1/Fc fusion protein, which blocks all VEGF isoforms, led to significant suppression of both pathological and physiological neovascularization. In addition, the targeted inactivation of monocyte lineage cells with clodronate-liposomes led to the suppression of pathological neovascularization. Conversely, the blockade of T lymphocyte-mediated immune responses with an anti-CD2 antibody exacerbated pathological neovascularization. These data highlight important molecular and cellular differences between physiological and pathological retinal neovascularization. During pathological neovascularization, VEGF164 selectively induces inflammation and cellular immunity. These processes provide positive and negative angiogenic regulation, respectively. Together, new therapeutic approaches for selectively targeting pathological, but not physiological, retinal neovascularization are outlined.

Animals↗
PubMed2003

Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease.

Retinal ischemia can cause vision-threatening pathological neovascularization. The mechanisms of retinal ischemia are not fully understood, however. Here we have shown that leukocytes prune the retinal vasculature during normal development and obliterate it in disease. Beginning at postnatal day 5 (P5) in the normal rat, vascular pruning began centrally and extended peripherally, leaving behind a less dense, smaller-caliber vasculature. The pruning was correlated with retinal vascular expression of intercellular adhesion molecule-1 (ICAM-1) and coincided with an outward-moving wave of adherent leukocytes composed in part of cytotoxic T lymphocytes. The leukocytes adhered to the vasculature through CD18 and remodeled it through Fas ligand (FasL)-mediated endothelial cell apoptosis. In a model of oxygen-induced ischemic retinopathy, this process was exaggerated. Leukocytes used CD18 and FasL to obliterate the retinal vasculature, leaving behind large areas of ischemic retina. In vitro, T lymphocytes isolated from oxygen-exposed neonates induced a FasL-mediated apoptosis of hyperoxygenated endothelial cells. Targeting these pathways may prove useful in the treatment of retinal ischemia, a leading cause of vision loss and blindness.

Animals↗
PubMed2003

Retention of dye after indocyanine Green-assisted internal limiting membrane peeling.

PURPOSE: To describe the long-term retention of indocyanine green (ICG) in the fundus after ICG-assisted internal limiting membrane peeling. DESIGN: Case report. Two patients underwent vitrectomy including ICG-assisted internal limiting membrane peeling. The fundus was examined with a 780-nm infrared illumination of a scanning laser ophthalmoscope after surgery. RESULTS: No ICG staining of the fundus was visible ophthalmoscopically. Examination with a scanning laser ophthalmoscope, however, detected fluorescence from residual ICG until 6 months after surgery in case 1 and 9 months in case 2. No complication related to the residual ICG was observed. CONCLUSIONS: The results suggested that ICG remains in the fundus for a long period after surgery. Clearance of the dye from the diabetic retina may be prolonged.

Aged↗