Biomedical subjects

Y Ogura

Publications and source records attributed to Y Ogura.

At least 19 recordsLinked to original sources

PubMed2000

Human Nod1 confers responsiveness to bacterial lipopolysaccharides.

The immune response to microbial pathogens is initiated by recognition of specific pathogen components by host cells both at the cell surface and in the cytosol. While the response triggered by pathogen products at the surface of immune cells is well characterized, that initiated in the cytosol is poorly understood. Nod1 is a member of a growing family of intracellular proteins with structural homology to apoptosis regulators Apaf-1/Ced-4 and a class of plant disease-resistant gene products. Here we show that bacterial lipopolysaccharides, but not other pathogen components tested, induced TLR4- and MyD88-independent NF-kappaB activation in human embryonic kidney 293T cells expressing trace amounts of Nod1. Nod2, another Nod family member, also conferred responsiveness to bacterial components but with a response pattern different from that observed with Nod1. As it was reported for plant disease-resistant R proteins, the leucine-rich repeats of Nod1 and Nod2 were required for lipopolysaccharide-induced NF-kappaB activation. A lipopolysaccharide binding activity could be specifically coimmunopurified with Nod1 from cytosolic extracts. These observations suggest that Nod1 and Nod2 are mammalian counterparts of plant disease-resistant gene products that may function as cytosolic receptors for pathogen components derived from invading bacteria.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Biodegradable scleral implant for controlled intraocular delivery of betamethasone phosphate.

We evaluated nail-like, biodegradable scleral implants as a controlled intraocular delivery system of betamethasone phosphate (BP) for the treatment of chronic uveitis using pigmented rabbits. The scleral implants, which contained 10% and 25% of BP (weight 8.5 mg; length 5 mm), were made of poly (D,L-lactide-co-glycolide) (PLGA). In vivo release and retinal toxicity after implantation were also studied in pigmented rabbits. The in vitro release studies demonstrated the 10% and 25% BP-loaded scleral implants released BP in a biphasic release pattern for at least 1 month. The BP concentrations in the vitreous and the retina/choroid after application of scleral implants in pigmented rabbit eyes stayed within the concentration range capable of suppressing inflammatory responses for over 1 month. The BP concentration was greater in the retina/choroid than in the vitreous throughout the study. No substantial toxic reactions in the retina were observed by electroretinography. Our findings suggest that the BP-loaded scleral implant may be a promising device for treatment of chronic uveitis.

Animals↗

PubMed2000

An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways.

Nod1 is an Apaf-1-like molecule composed of a caspase-recruitment domain (CARD), nucleotide-binding domain, and leucine-rich repeats that associates with the CARD-containing kinase RICK and activates nuclear factor kappaB (NF-kappaB). We show that self-association of Nod1 mediates proximity of RICK and the interaction of RICK with the gamma subunit of the IkappaB kinase (IKKgamma). Similarly, the RICK-related kinase RIP associated via its intermediate region with IKKgamma. A mutant form of IKKgamma deficient in binding to IKKalpha and IKKbeta inhibited NF-kappaB activation induced by RICK or RIP. Enforced oligomerization of RICK or RIP as well as of IKKgamma, IKKalpha, or IKKbeta was sufficient for induction of NF-kappaB activation. Thus, the proximity of RICK, RIP, and IKK complexes may play an important role for NF-kappaB activation during Nod1 oligomerization or trimerization of the tumor necrosis factor alpha receptor.

Adaptor Proteins, Signal Transducing↗

PubMed2000

Long-term sustained release of ganciclovir from biodegradable scleral implant for the treatment of cytomegalovirus retinitis.

The previous scleral implant composed of poly(D, L-lactide-co-glycolide) with ganciclovir (GCV) had some disadvantages such as the second burst in the late phase of release. In this study, the GCV release rate from scleral implants was modified by blending poly(D,L-lactide) (PLA) of two different molecular weights. The scleral implants were prepared by blending PLA-70000 (molecular weight: 70000) and PLA-5000 (molecular weight: 5000) or PLA-130000 (molecular weight: 130000) and PLA-5000 at weight ratios of 100/0, 95/5, 90/10, 80/20, and 0/100. In vitro release tests were performed in 0.1 M phosphate-buffered solution (pH 7.4) at 37 degrees C. An increase in the blended amount of PLA-5000 clearly accelerated the GCV release and the onset of the second burst in the late phase of release tended to delay. The two implants both prepared at a blend ratio of 80/20 successfully prevented the second burst and the GCV release profiles followed the pseudozero-order kinetics after the initial burst as resulting from a diffusional mechanism following Higuchi's equation. Duration of the sustained GCV release could be controlled by changing the blending ratio of high and low molecular weight PLA. The 25% GCV-loaded scleral implants composed of PLA-70000 and PLA-5000 with a blending ratio of 80/20 were implanted in pigmented rabbit eyes. The GCV concentrations in the vitreous after implantation of PLA-70000/PLA-5000 scleral implant with a blending ratio of 80/20 were maintained in the range of effective level for 6 months without a significant burst. Our results suggest that the blended implants are promising for the intraocular controlled drug delivery over a period of several months to one year to treat cytomegalovirus retinitis.

Animals↗

PubMed2000

Protective effects of selectin ligands/inhibitor (SKK-60060) against retinal ischemia-reperfusion injury.

A newly developed selSep;71(3)28 to block P- and L-selectins in vitro. We examined its inhibition of leukocyte-endothelial interactions in vivo against retinal ischemia-reperfusion injury and protective effects on ischemia-induced retinal damage. Retinal ischemia was induced by temporary ligation of the optic sheath for 60 min in anesthetized pigmented rats. SKK-60060 was administered 5 min before reperfusion and 4, 12, 24 and 48 hr thereafter, and leukocyte dynamics in the retinal microcirculation were evaluated using acridine orange digital fluorography. After 7 days of reperfusion, ischemia-induced retinal damage was also assessed histologically.SKK-60060 treatment suppressed leukocyte rolling during the reperfusion period; their numbers in the SKK-60060-treated rats were reduced by 67.0% (P < 0. 01) and 53.2% (P < 0.01) at 12 and 24 hr, respectively. The subsequent leukocyte accumulation was also inhibited in SKK-60060-treated rats; accumulated leukocytes in the SKK-60060-treated rats were reduced by 72.8% (P < 0.01) and 53.4% (P < 0.01) at 12 and 24 hr, respectively. Retinal venous vasodilation in SKK-60060-treated rats were significantly suppressed at each time point (P < 0.05). Histological examination demonstrated protective effects of SKK-60060 on ischemia-induced retinal damage, which were more substantial in the inner retina (P < 0.01).SKK-60060 significantly inhibits the leukocyte rolling along the major retinal veins and their accumulation during the reperfusion period. These results suggest therapeutic potential of SKK-60060 for ischemia-reperfusion injury.

Animals↗

PubMed2000

Biodegradable scleral implant for intravitreal controlled release of ganciclovir.

BACKGROUND: The aims of this study were to develop biodegradable scleral implants that could overcome previously reported disadvantages such as an adverse burst in the late phase of release and to investigate the release profile of modified scleral implants in vitro and in vivo. METHODS: The modified scleral implants (weight 8.5 mg, length 5 mm) were made of mixtures of poly(DL-lactide) (PLA) with different molecular weights and contained 25 weight % of ganciclovir (GCV). The release of GCV was evaluated in vitro by spectrophotometry. Intravitreal GCV concentrations in vivo were measured by high-performance liquid chromatography following plug implantation in pigmented rabbits. The biocompatibility of the device was determined by indirect ophthalmoscopy and light microscopy. RESULTS: The in vitro release studies showed stable, long-term sustained and slow release. The in vivo release studies showed that the implants had long-term release in the diffusional phase of the triphasic release pattern and only a minor adverse burst of GCV in the late phase. No significant retinal toxicity was observed by histologic examination. CONCLUSION: Our findings showed that this newly modified scleral implant may provide suitable intravitreal drug delivery for treatment of cytomegalovirus retinitis.

Absorbable Implants↗

PubMed2000

Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability is mediated by intercellular adhesion molecule-1 (ICAM-1).

Two prominent vascular endothelial growth factor (VEGF)-induced retinal effects are vascular permeability and capillary nonperfusion. The mechanisms by which these effects occur are not completely known. Using a rat model, we show that intravitreous injections of VEGF precipitate an extensive retinal leukocyte stasis (leukostasis) that coincides with enhanced vascular permeability and capillary nonperfusion. The leukostasis is accompanied by the up-regulation of intercellular adhesion molecule-1 expression in the retina. The inhibition of intercellular adhesion molecule-1 bioactivity with a neutralizing antibody prevents the permeability and leukostasis increases by 79% and 54%, respectively. These data are the first to demonstrate that a nonendothelial cell type contributes to VEGF-induced vascular permeability. Additionally, they identify a potential mechanism for VEGF-induced retinal capillary nonperfusion.

Acridine Orange↗

PubMed2000

In vivo evaluation of leukocyte dynamics in the retinal and choroidal circulation

We have developed a new method to visualize leukocytes and evaluate their kinetics in the chorioretinal microcirculation of the living eyes. Nuclear staining dyes and a scanning laser ophthalmoscope were used to image leukocytes in the fundus. Acridine orange was used to visualize leukocytes in the retinal microcirculation. For imaging leukocytes in the choroid, indocyanine green was injected intravenously. Dynamics of leukocytes in the capillaries of the retina and choroid were quantitatively estimated in monkeys and rats. This method also allowed evaluation of leukocyte-endothelial interactions, such as rolling or firm adhesion, in vivo.Acridine orange leukocyte fluography was used to study leukocyte dynamics in the following experimentally induced microcirculatory disturbances of the retina: (1) interferon-associated retinopathy, (2) ischemia-reperfusion injury of the retina, and (3) experimental diabetes mellitus.(1) Interferon-associated retinopathySystemic administration of interferon alpha enhanced leukocyte-endothelial interactions in the retina, which resulted in leukocyte rolling and entrapment in the retinal capillary beds. Leukocyte accumulation was also detected in the lung. The entrapment or accumulation of leukocytes in the microcirculation was inhibited by simultaneous administration of corticosteroids or other agents. These results suggested that leukocytes play a major role in the development of adverse effects of interferon, such as retinopathy or interstitial pneumonia.(2) Ischemia-reperfusion injury of the retinaDuring reperfusion period after transient (60 min) retinal ischemia by optic nerve ligation, the rolling of leukocytes in the retinal veins was prominent and numerous leukocytes were trapped in the retinal capillaries. The number of rolling leukocytes was at a maximum 12 hours after reperfusion. Leukocyte entrapment peaked at 24 hours after reperfusion. By blocking adhesion molecules on the vascular endothelium, these leukocyte-endothelial interactions were effectively inhibited. Postischemic retinal atrophy was also inhibited by blocking adhesion molecules. These results suggested that leukocytes may be major players in the pathophysiology of ischemia reperfusion injury of the retina.(3) Experimental diabetes mellitusLeukocyte dynamics in the retina were studied in streptozotocin-induced diabetes and spontaneous diabetes (OLETF rats). In both diabetic models, leukocyte entrapment in the retinal capillaries was increased even in the early stages of diabetes. Fluorescein angiography revealed that trapped leukocytes disturbed the regional capillary blood flow in the downstream. Enhanced expression of adhesion molecules was observed in the capillary endothelium of the retina in the diabetic rats. Leukocyte entrapment in the retinal capillaries might cause microvascular occlusions and dysfunction, in turn causing diabetic retinopathy.

Journal Article↗

PubMed2000

Haemophilus parainfluenzae antigen and antibody in children with IgA nephropathy and Henoch-Schönlein nephritis.

Although the pathogenesis of immunoglobulin A (IgA) nephropathy and Henoch-Schönlein nephritis (HSN) remains uncertain, there is substantial evidence that they are immune complex-mediated diseases. Recently, Haemophilus parainfluenzae antigens were shown in the glomerular mesangium of adult patients with IgA nephropathy, and greater levels of IgA antibody against H parainfluenzae were also shown in the sera of adult patients with IgA nephropathy. The present study was performed to detect H parainfluenzae antigens and antibody against H parainfluenzae in children with IgA nephropathy and HSN. H parainfluenzae antigens in the mesangium were examined by indirect immunofluorescence, and antibody against H parainfluenzae was examined by enzyme-linked immunosorbent assay. Diffuse global staining of the mesangium with rabbit antisera against H parainfluenzae was shown in 10 of the 32 patients (31%) with IgA nephropathy and 12 of the 34 patients (35%) with HSN. Conversely, only 2 of the 47 patients (4%) with other renal diseases showed staining of glomeruli with rabbit antisera against H parainfluenzae (IgA nephropathy versus other renal diseases, P = 0.003; HSN versus other renal diseases, P = 0.0006). Patients with IgA nephropathy and those with HSN showed significantly greater levels of plasma IgA1 antibody against H parainfluenzae than patients with other renal diseases (IgA nephropathy versus other renal diseases, P = 0.008; HSN versus other renal diseases, P = 0.025). These findings suggest that H parainfluenzae has a role in the cause of these two conditions in a subset of patients.

Adolescent↗

PubMed2000

Preoperative diagnosis of gallbladder torsion by magnetic resonance cholangiopancreatography.

The patient was a 78-year-old woman who was diagnosed as having gallbladder torsion preoperatively. This is the first reported case diagnosed by magnetic resonance cholangiopancreatography (MRCP). Signs and symptoms of this condition are often subtle. Radiologic evaluation by ultrasonography and computed tomography (CT) showed acute cholecystitis with stone. Drip-infusion cholangiography CT failed to outline the gallbladder, and distortion of the extrahepatic bile ducts and interruption of the cystic duct were observed. MRCP showed 1) a v-shaped distortion of the extrahepatic bile ducts due to traction by the cystic duct, 2) tapering and twisting interruption of the cystic duct, 3) a distended and enlarged gallbladder that was deviated to the midline of the abdomen, and 4) a difference in intensity between the gallbladder and the extrahepatic bile ducts and the cystic duct. A definitive diagnosis of gallbladder torsion (volvulus) was made by MRCP preoperatively. If treated surgically, gallbladder detorsion before cholecystectomy is a helpful technique to avoid bile duct injury. This condition should be suspected in elderly women with acute cholecystitis or acute abdominal pain of unknown origin, and MRCP may be very useful in making a definitive diagnosis.

Aged↗

PubMed2000

Radiolabeled annexin V imaging: diagnosis of allograft rejection in an experimental rodent model of liver transplantation.

PURPOSE: To assess the value of imaging rejection-induced apoptosis with technetium 99m and annexin V, a human protein-based radiopharmaceutical used in the diagnosis of acute rejection of a liver transplant, in a well-characterized rodent model of orthotopic liver transplantation. MATERIALS AND METHODS: 99mTc-radiolabeled annexin V was intravenously administered to six allografted (immunologically mismatched) and five isografted (immunologically matched) recipient rats on days 2, 4, and 7 after orthotopic liver transplantation. Animals were imaged 1 hour after injection of 0.2-2.0 mCi (8.0-74.0 MBq) of radiolabeled annexin V by use of clinical nuclear scintigraphic equipment. RESULTS: All animals in the allografted group demonstrated marked increases of 55% and 97% above the activity in the isografted group in hepatic uptake of annexin V on days 4 and 7, respectively. Severe acute rejection was histologically detected in all allografted livers on day 7. There was no histologic evidence of acute rejection in isografted animals. Dynamic hepatobiliary imaging with 99mTc and mebrofenin, an iminodiacetic acid derivative, demonstrated no correlation with the presence or absence of acute rejection or with annexin V uptake. CONCLUSION: Noninvasive imaging with radiolabeled annexin V is more sensitive and specific than imaging with 99mTc-mebrofenin in the diagnosis of acute rejection of a liver transplant.

Acute Disease↗

PubMed2000

Leukocyte-endothelial cell interactions in diabetic retina after transient retinal ischemia.

Diabetes is associated with increased neural damage after transient cerebral ischemia. Recently, leukocytes, which are thought to play a central role in ischemia-reperfusion injury, have been suggested to be involved in exacerbated damage after transient ischemia in diabetic animals. The present study was designed to clarify whether the anticipated worse outcome after transient cerebral ischemia in diabetic animals was due to augmented leukocyte-mediated neural injury. Using rats with streptozotocin-induced diabetes of 4-wk duration, we investigated leukocyte-endothelial cell interactions during reperfusion after a transient 60-min period of retinal ischemia. Unexpectedly, postischemic diabetic retina showed no active leukocyte-endothelial cell interactions during reperfusion. The maximal numbers of rolling and accumulating leukocytes in diabetic retina were reduced by 73.6 and 41.2%, respectively, compared with those in nondiabetic rats. In addition, neither preischemic insulin treatment of diabetic rats nor preischemic glucose infusion of nondiabetic rats significantly influenced leukocyte-endothelial cell interactions during reperfusion. The present study demonstrated that high blood glucose concentration before induction of ischemia did not exacerbate leukocyte involvement in the postischemic retinal injury. Furthermore, diabetic retina showed suppressed leukocyte-endothelial cells interactions after transient ischemia, perhaps due to an adaptive mechanism that developed during the period of induced diabetes.

Animals↗

PubMed2000

Interactions between blood cells and retinal endothelium in endotoxic sepsis.

Platelets and leukocytes are thought to play a leading role in the pathogenesis of many inflammatory conditions. To recruit flowing blood cells to the inflammatory region, it would be necessary for them to interact with vascular endothelial cells. Recently, many reports have indicated the resistance of spontaneous hypertensive rats (SHR) to endotoxic sepsis. Their resistance might be derived from suppressed interaction between these blood cells and endothelial cells. Therefore, SHR and age-matched Wistar-Kyoto rats (WKY) were induced with endotoxic sepsis by intravenous injection of lipopolysaccharide (LPS). At 4, 12, 24, and 48 hours after induction, leukocyte-endothelial interactions in the retina were evaluated in vivo with acridine orange digital fluorography. Fluorescently labeled platelets were also injected to investigate platelet-endothelial interactions in the retina in endotoxic sepsis. Leukocyte rolling in SHR after LPS injection was significantly suppressed; the maximum number of rolling leukocytes was reduced by 80.1% at 12 hours after LPS injection in SHR compared with WKY. Subsequent leukocyte infiltration into the vitreous cavity was significantly inhibited in SHR. Furthermore, platelet-endothelial interactions in the retina were also suppressed in SHR treated with LPS. The maximum numbers of rolling and adherent platelets were reduced by 59.5% and 62.6%, respectively, in SHR compared with WKY. In both strains, leukocyte- and platelet-endothelial interactions were substantially inhibited by the blocking of P-selectin. These suppressed interactions could contribute to the reduction of leukocyte- and platelet-mediated tissue injury in endotoxic sepsis in SHR, resulting in their resistance to endotoxemia.

Animals↗

PubMed2000

Oxidation and reduction of nitrite ion in the TiO2 photo-induced catalytic reaction.

During a photo-induced catalytic reaction under near UV irradiation to an aqueous suspension of Ti4O2, about 95% of NO2- was oxidized to NO3-, but NH4+ was not detected. The oxidation was inhibited by the addition of mannitol or under anaerobic conditions. The nitration of HPA was observed in the presence of t-buthanol, suggesting the formation of ONOO. An ESR spectrum gave a triplet signal at g = 2.041,in the presence of NO2-, mannitol, FeSO4, and MGD, indicating the reduction of NO2- to NO.

Catalysis↗

PubMed2000

Apoptosis is associated with formation and persistence of the embryonic fissure.

PURPOSE: The role of apoptosis in the transitory ocular embryonic structures has not been clarified yet, therefore, in the present study we focused on one of the transitory ocular structures, the embryonic fissure. To elucidate the developmental mechanism of the embryonic fissure, we observed cell death by apoptosis in the optic cup during early development in mice. METHODS: Pairs of C57BL6N/Jcl mice, each comprising an estrous female and a potent male, were caged together overnight. Females that had vaginal plugs the next morning were considered at day 0 of pregnancy. The embryos or fetuses were removed by laparotomy on days 9, 10, 11, 12, 13, 14, 16, and 18 of gestation. Tissue blocks of the eyes were fixed and embedded in paraffin wax. Serial frontal sections of the eye were cut and stained with the TUNEL method and then counterstained by hematoxylin or methyl green solution. We examined TUNEL-positive cells in the optic cup by light microscopy. RESULTS: TUNEL-positive cells were seen at the lower nasal side of the optic cup, corresponding to the presumed embryonic fissure area, on day 9 of gestation before the formation of the embryonic fissure. Many TUNEL-positive cells were present at the lips of the embryonic fissure on days 10, 11, and 12. In contrast, TUNEL-positive cells were not detectable in the corresponding area on day 13 after the complete closure of the embryonic fissure. CONCLUSIONS: Apoptosis is anatomically closely associated, and appears to be essential for the formation and persistence of the embryonic fissure.

Animals↗

PubMed2000

Chemoprevention of biliary carcinogenesis in syrian hamsters by the novel carboxamide derivative IS-741 after initiation with N-nitrosobis(2-oxopropyl)amine (BOP).

To elucidate the possible inhibitory effect of a novel carboxamide derivative (IS-741) on biliary carcinogenesis, Syrian hamsters were subjected to cholecystoduodenostomy and ligation of the distal end of the common duct, and then given a regular diet (group I) or a diet containing 200 p.p.m. of IS-741 (group II). All hamsters were subcutaneously injected with N-nitrosobis(2-oxopropyl)amine until 10 weeks after surgery, and continued to feed on their respective dietary regimen until termination of the experiment at 16 weeks after surgery. Biliary adenocarcinomas were evaluated histologically. Non-cancerous and cancerous hepatobiliary tract tissues were analyzed for phospholipase A(2) (PLA(2)) activity, myeloperoxidase (MPO) activity, and the concentrations of prostaglandin (PG), i.e., prostaglandin E(2), 6-ketoprostaglandin F(1)alpha and thromboxane B(2). IS-741 significantly inhibited the development and multiplicity of hepatobiliary adenocarcinomas and reduced the proliferating cell nuclear antigen labeling indices in non-cancerous hepatobiliary tissues, compared with group I. The anti-cancerous effect of IS-741 was associated with a significant inhibition of PLA(2) and MPO levels in non-cancerous tissues of the extrahepatic biliary tract and the liver, and in cancerous tissue of the liver. Furthermore, IS-741 reduced the production of PGs in non-cancerous hepatobiliary tissues, compared with group I. Although the precise mechanism of action of IS-741 in preventing biliary tumorigenesis remains to be elucidated, it is likely to be related to modulation of arachidonic acid metabolism and/or suppression of neutrophil accumulation.

6-Ketoprostaglandin F1 alpha↗

PubMed2000

Administration of 17beta-estradiol attenuates retinal ischemia-reperfusion injury in rats.

PURPOSE: Accumulating evidence has suggested that 17beta-estradiol exerts protective effects against ischemic damage in various organs. In addition, leukocytes that accumulate in postischemic tissues are thought to play a central role in ischemia-reperfusion injury. This study was designed to evaluate quantitatively the inhibitory effects of 17beta-estradiol on leukocyte accumulation during ischemia-reperfusion injury and on subsequent retinal damage after transient retinal ischemia. METHODS: Transient (60 minutes) retinal ischemia was induced in male rats by temporary ligation of the optic nerve. Thirty minutes before induction of ischemia, 17beta-estradiol (0.1 mg/kg) was administered intraperitoneally. At 6, 12, 24, and 48 hours after reperfusion, leukocyte accumulation in the retina was evaluated in vivo by means of acridine orange digital fluorography. Histologic and electroretinographic (ERG) studies were carried out to evaluate retinal damage. RESULTS: Treatment with 17beta-estradiol significantly inhibited postischemic leukocyte accumulation; the maximum number of accumulating leukocytes was reduced by 35.7% at 24 hours after reperfusion (P = 0.01). Histologic examination showed that administration of 17beta-estradiol significantly reduced retinal damage, which was most obvious in the inner retina, 168 hours after reperfusion (P = 0.0001). ERG studies at 12 and 168 hours after reperfusion showed that recovery of the b-wave amplitude was significantly improved with treatment of 17beta-estradiol (P = 0.023). CONCLUSIONS: The present study demonstrated the inhibitory effects of 17beta-estradiol on leukocyte accumulation and subsequent tissue injury during retinal ischemia-reperfusion injury.

Acridine Orange↗

PubMed2000

PKC-beta inhibitor (LY333531) attenuates leukocyte entrapment in retinal microcirculation of diabetic rats.

PURPOSE: The activity of protein kinase C (PKC), preferentially beta isoform of PKC, has been shown to be elevated in the diabetic retina. Recently, LY333531, a specific inhibitor of PKC-beta, has been reported to improve the decrease of retinal blood flow in early diabetes. Increased leukocyte entrapment has been suggested to be involved in blood flow disturbances in the early diabetic retina. This study was designed quantitatively to evaluate leukocyte entrapment in the retinal microcirculation of diabetic rats and the effect of LY333531 on leukocyte entrapment. METHODS: Diabetes was induced in male Long-Evans rats by intraperitoneal injection of streptozotocin (60 mg/kg). LY333531 (0.1, 1.0, or 10.0 mg/kg/d) was administered orally during a 4-week diabetic period. Leukocyte entrapment in the retinal microcirculation was quantitatively evaluated in vivo with acridine orange digital fluorography. RESULTS: The number of leukocytes trapped in the retinal microcirculation of diabetic rats (mean +/- SEM; 14.3 +/- 1.3 cells/mm2) was significantly increased, compared with nondiabetic control rats (7.5 +/- 0.3 cells/mm2; P < 0.0001). Oral administration of LY333531 significantly decreased the number of leukocytes trapped in the retinal microcirculation of diabetic rats (10.9 +/- 0.6, 11.3 +/- 0.7, and 10.4 +/- 0.4 cells/mm2 with LY333531 0.1, 1.0, and 10.0 mg/kg/d, respectively; P < 0.05). CONCLUSIONS: Treatment with LY333531 attenuated the increase of leukocyte entrapment in the retinal microcirculation during the period of early diabetes. This effect may contribute to the improvement of abnormal retinal blood flow in early diabetes with LY333531. LY333531 might have a therapeutic efficacy in preventing microcirculatory flow disturbances by trapped leukocytes in the early diabetic retina.

Acridine Orange↗