[show abstract][hide abstract] ABSTRACT: Neuroinflammation is involved in the death of retinal ganglion cells (RGCs) after optic nerve injury. The purpose of this study was to determine whether systemic simvastatin can suppress neuroinflammation in the optic nerve and rescue RGCs after the optic nerve is crushed. Simvastatin or its vehicle was given through an osmotic minipump beginning one week prior to the crushing. Immunohistochemistry and real-time PCR were used to determine the degree of neuroinflammation on day 3 after the crushing. The density of RGCs was determined in Tuj-1 stained retinal flat mounts on day 7. The effect of simvastain on the TNF-α-induced NF-κB activation was determined in cultured optic nerve astrocytes. On day 3, CD68-positive cells, most likely microglia/macrophages, were accumulated at the crushed site. Phosphorylated NF-κB was detected in some astrocytes at the border of the lesion where the immunoreactivity to MCP-1 was intensified. There was an increase in the mRNA levels of the CD68 (11.4-fold), MCP-1 (22.6-fold), ET-1 (2.3-fold), GFAP (1.6-fold), TNF-α (7.0-fold), and iNOS (14.8-fold) genes on day 3. Systemic simvastatin significantly reduced these changes. The mean ± SD number of RGCs was 1816.3±232.6/mm(2) (n = 6) in the sham controls which was significantly reduced to 831.4±202.5/mm(2) (n = 9) on day 7 after the optic nerve was crushed. This reduction was significantly suppressed to 1169.2±201.3/mm(2) (P = 0.01, Scheffe; n = 9) after systemic simvastatin. Simvastatin (1.0 µM) significantly reduced the TNF-α-induced NF-κB activation in cultured optic nerve astrocytes. We conclude that systemic simvastatin can reduce the death of RGCs induced by crushing the optic nerve possibly by suppressing astroglial NF-κB activation.
PLoS ONE 01/2014; 9(1):e84387. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: To assess efficacy of the conservative management of patients with congenital dacryocystocele.
This was a retrospective case series involving six sides of five infants with a dacryocystocele treated at Osaka Kaisei Hospital, Osaka, Japan. The conservative management protocol consisted of the application of warm compresses and massage over the mass, with the addition of antibiotics when dacryocystitis developed. Patient age at the time of resolution, presence of retrograde outflow of contents of dacryocystoceles from the puncta, and development of dacryocystitis were recorded.
The dacryocystocele was unilateral in four patients and bilateral in one patient. A nasal cyst was present in four patients without respiratory distress. The median patient age at the time of the diagnosis was 7 days (range 2-10 days). Conservative management was selected in all patients, and the dacryocystocele was resolved in all patients at a median patient age of 14.5 days (range 11-105 days). Two sides developed dacryocystitis, which resolved in a few days with antibiotic treatment. In those two sides, rupture of the dacryocystoceles to the common canaliculus with retrograde discharge of the contents from the puncta before the dacryocystitis developed was noted. For the other four treated sides, no such discharge or development of dacryocystitis was observed.
The findings of this study show that a dacryocystocele has a good chance of resolving spontaneously with conservative management and careful observation, and that rupture of the dacryocystocele to the common canaliculus might be an important precursor of dacryocystitis.
[show abstract][hide abstract] ABSTRACT: PURPOSE: To report a case of pseudo-unilateral occult macular dystrophy (OMD) with an Arg45Trp mutation in the RP1L1 gene and had unilateral functional changes for about 9 years. CASE REPORT: A 64-year-old woman with a decimal visual acuity of 1.0 in both eyes complained about difficulties with visual tasks because of presbyopia. At the age of 65 years, her visual acuity in the left eye decreased to 0.2, while that in the right eye was 0.7. The fundus of both eyes was normal except for drusen. After 10 years and at the age of 75 years, her visual acuity in the right eye decreased to 0.3. Focal macular electroretinograms (ERGs) at this time were severely attenuated in both eyes, while the full-field ERGs were within normal limits. Ophthalmoscopy showed that the fundus of both eyes was still normal. Genetic analysis revealed a heterozygous mutation, Arg45Trp, in the RP1L1 gene. CONCLUSIONS: These findings indicate that the phenotype in some cases of OMD with an Arg45Trp mutation in the RP1L1 gene can be unilateral for a considerable period.
[show abstract][hide abstract] ABSTRACT: The diagnosis of amyotrophic lateral sclerosis (ALS) is difficult due to lack of definitive biomarkers. Our aim was to identify characteristic serum protein patterns that could provide candidate biomarkers for ALS. We divided mutant superoxide dismutase-1 (SOD1)(H46R) rats into three groups based on disease progression: pre-symptom (90 days), onset, and end-stage. After separation of serum proteins using two-dimensional electrophoresis, we selected clear protein spots and identified two candidate proteins-inter-alpha-trypsin inhibitor heavy chain H4 (ITIH4) and glutathione peroxidase 3 (Gpx3). The 120 kDa ITIH4 increased at the onset of the disease and the 85 kDa ITIH4, a cleaved form, at the end-stage in the sera of the SOD1(H46R) rats. Expression of the 85 kDa ITIH4 was substantial in ALS compared with controls or patients with muscular dystrophy, Alzheimer diseases, or Parkinson diseases. The Gpx3 protein levels in the sera of SOD1(H46R) rats were upregulated pre-symptom and gradually decreased as the disease progressed. The Gpx3 protein levels were lower in the sera of the patients with ALS than in other diseases. These results indicate that ITIH4 and Gpx3 are potential biomarkers for ALS.
Journal of Neurology 02/2013; · 3.58 Impact Factor
[show abstract][hide abstract] ABSTRACT: To report the short-term efficacy and safety of the transfer of an Ahmed glaucoma valve (AGV™) tube from the vitreous into the anterior chamber, in a patient with neovascular glaucoma who had undergone pars plana AGV implantation and ultimately needed a silicone oil tamponade.
A 41-year-old male with proliferative diabetic retinopathy in both eyes was referred to us for treatment in December 2009. Although the patient previously underwent several surgeries, he ultimately lost vision in his right eye. His left eye suffered from neovascular glaucoma after undergoing a pars plana vitrectomy for tractional retinal detachment. After several vitreous and glaucoma surgeries, the patient underwent implantation of a pars plana AGV™. Postoperatively, although his intraocular pressure was stabilized at approximately 10 mmHg, he had repeated vitreous hemorrhage and hyphema without improvement. He ultimately underwent PPV with a silicone oil tamponade and at the same time, the AGV™ tube was pulled out from the vitreous and inserted into the anterior chamber in order to avoid complications caused by the silicone oil.
At 19 months postoperative, the patient's intraocular pressure had stabilized at 10 mmHg with no recurrence of vitreous hemorrhage and hyphema. Eventually, he lost vision in his left eye because of cerebral hemorrhage.
The findings show that insertion of a pars plana AGV™ tube into the anterior chamber in a patient undergoing a silicone oil tamponade is both effective and safe in the short-term.
[show abstract][hide abstract] ABSTRACT: This case report describes a case of Alagille syndrome with developing intraocular lens subluxation and rhegmatogenous retinal detachment 4 years after cataract surgery. A 15-year-old female patient with Alagille syndrome-associated cataracts in both eyes underwent phacoemulsification aspiration and intraocular lens implantation. Four years postoperative, intraocular lens subluxation developed in her left eye. For treatment, extraction of the dislocated intraocular lens, anterior vitrectomy, and intraocular lens fixation was performed. Three weeks later, the patient developed rhegmatogenous retinal detachment, which was well-treated by pars plana vitrectomy. Cataract surgery needs to be performed carefully in patients with Alagille syndrome due to the weakness of the zonule of Zinn. Careful postoperative observation is necessary for patients with Alagille syndrome who have undergone intraocular surgery in order to facilitate early detection of a possible rhegmatogenous retinal detachment.
[show abstract][hide abstract] ABSTRACT: To investigate whether the P2X7 receptor is involved in retinal ganglion cell (RGC) death after the intraocular pressure (IOP) is elevated in rats.
After the IOP was elevated to 90 mmHg for 1 h, the rats were subsequently administered oxidized adenosine triphosphate (OxATP) and brilliant blue G (BBG) as P2X7 antagonists. The rats were euthanized 7 days after IOP elevation for histologic evaluation and at 1, 3, and 7 days after IOP elevation to immunostain for the P2X7 receptor and neuron-specific class III β-tubulin in the retina. Changes in P2X7 receptor expression were measured in total retina extracts using western blot analysis. Quantitative real-time PCR was also performed using the entire retina to determine whether the P2X7 receptor is involved in upregulating tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 at 1, 2, and 3 days after the IOP was elevated.
RGC density and the inner plexiform layer thickness significantly decreased 7 days after IOP elevation, but were dose-dependently preserved when treated with OxATP or BBG. P2X7 immunoreactivity in the RGCs increased after IOP elevation, with the peak occurring from day 1 through day 3. Protein levels of P2X7 receptor were significantly increased 1, 2, and 3 days after IOP elevation. The messenger ribonucleic acid expression of the P2X7 receptor, TNF-α, IL-1β, and IL-6 was significantly upregulated in the retina after IOP elevation, and was suppressed by treatment with OxATP.
These results suggest the expression of the P2X7 receptor is upregulated in the retina after IOP elevation, leading to RGC death. Upregulation of TNF-α, IL-1β, and IL-6 might be involved in this mechanism of RGC death. Furthermore, P2X7 antagonists may prevent RGC death after IOP elevation.
[show abstract][hide abstract] ABSTRACT: We investigated whether P2X(7) antagonists rescue retinal ganglion cells (RGCs) in culture and after optic nerve crush (ONC) injury. Rats were sacrificed 7 days after retrograde labeling of RGCs with 4',6-diamidino-2-phenylindole (DAPI), and the retinas were enzymatically dissociated in vitro and incubated with P2X(7) antagonists or agonists for 3 days. Adenosine triphosphate (ATP) and benzoylbenzoyl ATP were used as P2X(7) agonists, and oxidized ATP and brilliant blue G were used as P2X(7) antagonists. DAPI-positive and calcein-positive RGCs were counted to determine the number of living cells. We observed that RGCs were preserved when treated with P2X(7) antagonists, as compared with the controls. In contrast, P2X(7) agonists significantly decreased the number of viable RGCs. In vivo, P2X(7) antagonists at various doses were injected into the vitreous body immediately after ONC injuries in rats. Surviving RGCs were stained with anti-neuron-specific β-tubulin antibody in flat-mounted retinas. RGCs were observed to decrease to 61% of baseline 7 days after ONC injury, whereas RGCs were significantly preserved when P2X(7) antagonists were applied. When P2X(7) receptor expression was examined immunohistochemically in rat retinas after ONC, the retinal expression of the P2X(7) receptors was observed to be upregulated after ONC and peaked on day 3. Meanwhile, P2X(7) antagonists suppressed this upregulation. Collectively, these results suggest that P2X(7) antagonists prevent loss of RGCs after ONC, and that this protective effect is possibly mediated through suppressing the upregulation of retinal P2X(7) expression.
[show abstract][hide abstract] ABSTRACT: The aim of this study was to verify the correlation between mean blur rate (MBR) obtained with CCD-equipped laser speckle flowgraphy (LSFG) and capillary blood flow (CBF) obtained by the hydrogen gas clearance method in rabbit optic nerve head (ONH). Using Japanese white rabbits under systemic anesthesia, a hydrogen electrode was inserted an area of the ONH free from superficial capillaries. MBR was measured with LSFG near the hydrogen electrode. CBF and MBR were measured in the range of 32.4-83.5 mL/min/100 g and 3.5-6.0, respectively. MBR and CBF were significantly correlated (r = 0.73, P<0.01, n = 14). After inhalation of carbon dioxide (CO(2)) or intravenous administration of endothelin-1 (ET-1), MBR and CBF were changed in the relative range of 0.74-1.27 and 0.76-1.35, respectively. The relative changes in MBR and CBF induced by CO(2) and ET-1 were also significantly correlated (r = 0.67, P<0.01). The current results suggest that MBR may correlate with CBF and also change with CBF, as an index of blood flow in the ONH, linearly.
Experimental Eye Research 12/2012; · 3.03 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate the involvement of glial cells in the autoregulation of optic nerve head (ONH) blood flow in response to elevated intraocular pressure (IOP).
Rabbit eyes were treated with an intravitreal injection of l-2-aminoadipic acid (LAA), a gliotoxic compound. Twenty-four hours after the injection IOP was artificially elevated from a baseline of 20 to 50 or 70 mm Hg and maintained at each IOP level for 30 minutes. ONH blood flow was measured by laser speckle flowgraphy every 10 minutes. Ocular perfusion pressure (OPP) was calculated to investigate the relationship between ONH blood flow and OPP. To evaluate the effects of LAA on the function and morphology of retinal neurons and glial cells, electroretinogram (ERG) was monitored after injections of LAA (2.0 and 6.0 mM) or saline as a control. Histologic and immunohistochemical examinations were then performed.
In the LAA-treated eyes, histologic changes selectively occurred in the retinal Müller cells and ONH astrocytes. There was not any significant reduction of amplitude or elongation of implicit time of each parameter in the ERG after LAA injection compared with control. ONH blood flow in LAA-treated eyes was significantly decreased with a reduction of OPP during IOP elevation to 50 and 70 mm Hg, whereas blood flow was maintained in control eyes during IOP elevation to 50 mm Hg.
These results indicate the involvement of glial ells in the autoregulation of ONH blood flow during IOP elevation.
[show abstract][hide abstract] ABSTRACT: The endothelins (ETs) cause reactive astrogliosis, which involves neuroinflammation and neurodegeneration in the central nervous system. The purpose of this study was to determine whether blocking the ET signals will protect retinal ganglion cells (RGCs) from optic nerve injury.
We studied the effect of pretreatment with BQ-123, an antagonist of ETA receptors, and BQ-788, an antagonist of ETB receptors, on the survival of RGCs after the optic nerve of rats was crushed. We also performed immunohistological evaluations and real-time PCR of the crushed site to determine the expressions of the ET-1, CD68, GFAP, TNF-α, and iNOS genes in the neuroinflammation of the optic nerves.
The mRNA levels of the ETB receptors were upregulated (5.6-fold) on day 7 after crushing the optic nerves. Cells expressing ETB receptors were recruited mainly to the crushed site where the immunoreactivity to GFAP was weak. These cells were also immuunoreactive to ETs and CD68, a constitutive marker of microglia/macrophages. In the adjacent areas, immunoreactivity to GFAP was intense. Crushing the optic nerve increased the mRNA levels of ET-1 (4.5-fold), CD68 (87.5-fold), GFAP (2-fold), TNF-α (480-fold), and iNOS (6-fold) on day 7. Pretreatment with BQ-788 significantly suppressed the upregulation of these genes and loss of RGCs on day 7, whereas BQ-123 failed to protect the RGCs.
These results suggest that the microglia/macrophages recruited to the crushed site are the possible cellular sources of the ETs, which caused reciprocal activation of astrocytes. Blocking the ETB receptors by BQ-788 rescued RGCs, most likely by attenuating neuroinflammatory events.
[show abstract][hide abstract] ABSTRACT: To examine the relationship between the extent of subarachnoid hemorrhage and intraocular hemorrhages in patients with subarachnoid hemorrhage.
A total, of 63 patients (25 men and 38 women, mean age 58 years). The subarachnoid hemorrhage quantity was graded according to the Fisher scale and compared with hemorrhages in the ocular fundus.
Either vitreous or preretinal hemorrhages in either one or both eyes (vitreous hemorrhages) were present in 16 patients (25%). Retinal hemorrhages in either one or both eyes (retinal hemorrhages) were present in 12 patients (19%). Intraocular hemorrhage was absent in the other 35 patients (56%). The incidence of vitreous hemorrhage tended to be higher than the incidence of retinal hemorrhage or of the absence of hemorrhage as the rate of subarachnoid hemorrhage increased (Kruskal-Wallis, p < 0.05). There was no significant correlation between retinal hemorrhages and the absence of hemorrhage in the Fisher grade IV chi2, p > 0.05).
The onset of vitreous hemorrhage appears to be related to the extent of subarachnoid hemorrhage but the onset of retinal hemorrhage is not.
[show abstract][hide abstract] ABSTRACT: We investigated the effects of hypercholesterolemia on optic nerve head (ONH) blood flow, visual function, and retinal histology in a rabbit model. Hypercholesterolemia was induced in rabbits by feeding them a high cholesterol (1%) diet for 12 weeks. Changes in blood pressure, intraocular pressure (IOP), and ONH blood flow were monitored at 6 and 12 weeks after treatment. The autoregulation of ONH blood flow as detected by laser speckle flowgraphy was verified by an artificial elevation of IOP at 12 weeks. Visually evoked potentials (VEPs) were also recorded and analyzed at 6 and 12 weeks. Finally, a histological examination as well as immunohistochemistry to endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) was performed. In the hypercholesterolemic rabbits, blood pressure, IOP, and ONH blood flow did not alter significantly throughout this study. The autoregulation of ONH blood flow against IOP elevation was found to be impaired at 12 weeks. The amplitudes of the first negative peak of VEPs were diminished. Both the density of the retinal ganglion cells and the thickness of the inner nuclear layer and photoreceptor cell layer were reduced. Immunoreactivity to eNOS was reduced and that to iNOS was enhanced in the hypercholesterolemic rabbits compared to those in the normal control rabbits. The results of this study show that hypercholesterolemia induces impairment in the autoregulation of ONH blood flow and deterioration in visual function and histology. Downregulation of eNOS activity might be one of the causes for impairment of the autoregulation. Enhanced activity of iNOS might be involved in the impaired visual function and histology.
Experimental Eye Research 12/2011; 93(6):818-24. · 3.03 Impact Factor
[show abstract][hide abstract] ABSTRACT: We have developed inorganically-coated all-trans retinoic acid (atRA) nanoparticles, nano-sized egg-like particles of atRA (NANOEGG®-atRA). The purpose of this study was to determine the effects of NANOEGG®-atRA on corneal wound healing in vivo and in vitro.
A rabbit corneal epithelial wound healing model was exposed to different concentrations of NANOEGG®-atRA. Wound healing was serially quantified as the ratio of fluorescein-stained area at the selected times to that at baseline. After wound closure, the barrier function of the cornea was determined using low concentrations of tropicamide. At the completion of the experiments, the corneal epithelium was histologically examined. For the in vitro studies, linear scratch wounds were made on cultured SV40-immortalized human corneal epithelial cells (HCE-T). Then, the cells were exposed to different concentrations of NANOEGG®-atRA, and wound healing was determined by the degree of closure of the scratch wound. In addition, the effects of NANOEGG®-atRA on the proliferation of HCE-T cells were determined by WST-8 assays.
Exposure to NANOEGG®-atRA decreased the injured area 24 hrs after the ablation. The maximum effect of NANOEGG®-atRA was observed at a concentration of 33 mM. Histologically, no abnormal or differentiated corneal epithelial cells were observed in the histological sections treated with NANOEGG®-atRA. The tropicamide-induced pupillary dilation was significantly slowed in the eyes treated with NANOEGG®-atRA. NANOEGG®-atRA at concentrations of 3.3 and 33 nM induced earlier wound closure in vitro, but did not induce proliferation of HCE-T cells.
NANOEGG®-atRA promotes wound healing and should be considered for the treatment of wounds of the corneal epithelium.
Albrecht von Graæes Archiv für Ophthalmologie 11/2011; 250(4):557-63. · 1.93 Impact Factor
[show abstract][hide abstract] ABSTRACT: The aim of this study was to determine the reasons why the intravitreal level of extracellular-superoxide dismutase (EC-SOD) increases in proliferative diabetic retinopathy patients by the investigation of two possibilities: first, change of EC-SOD expression in the retina; and secondly, leakage of EC-SOD through the endothelial monolayer by the treatment with endoplasmic reticulum (ER) stress inducers because ER stress is known to be involved in the vascular impairment in diabetic retinopathy. Intravitreous injection of tunicamycin in mice increased the permeability of tracer dye across retinal blood vessels while the retinal EC-SOD mRNA level was not changed. The leakage of EC-SOD through the retinal endothelial cell layer was elevated by the treatment with thapsigargin or tunicamycin. The expression of claudin-5 was significantly decreased by the treatment with the ER stress inducers. These phenomena were significantly suppressed by the pre-treatment of endothelial cells with a chemical chaperone 4-phenylbutyric acid. Our observations suggest that ER stress leads to the down-regulation of claudin-5 among tight junction proteins and may induce the elevation of endothelial permeability and leakage of EC-SOD into the vitreous body.
Free radical research 09/2011; 45(9):1083-92. · 2.22 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate the effects of gelatin hydrogel (GH) containing a chymase inhibitor (CI) on intraocular pressure (IOP) and conjunctival scarring in a canine model of glaucoma surgery.
Glaucoma surgery models were made in beagles. As the first experiment, GH was implanted. IOP was measured for 4 weeks, followed by histologic evaluation. As the second experiment, GH containing a CI or GH alone was implanted. IOP and bleb features were evaluated for 12 weeks. The densities of proliferative cell nuclear antigen (PCNA)-positive cells, fibroblasts, and mast cells were quantified. The mRNA levels of transforming growth factor-β (TGF-β) and chymase were determined by real-time PCR.
In the first experiment, IOP was significantly lower in the eyes treated with GH than that in the control eyes. The conjunctival area normalized by the scleral area was reduced in the treated eyes. In the second experiment, IOP reduction was maintained for 12 weeks in the eyes treated with GH containing a CI, but not in the eyes treated with GH alone. In addition, the bleb score was larger, whereas the adhesion score and densities of PCNA-positive cells, fibroblasts, mast cells, and chymase-positive cells were lower in the eyes treated with GH containing a CI. The mRNA levels of TGF-β and chymase were significantly decreased in the eyes treated with GH containing a CI.
Implanting GH alone maintained IOP reduction, whereas GH containing a CI enhanced the IOP-reducing effect by suppressing cell proliferation. This drug delivery system might be useful for maintaining filtering blebs for a longer duration after glaucoma surgery.
[show abstract][hide abstract] ABSTRACT: Modulation of enzyme activity through nitrosylation has recently been identified as a new physiological activity of nitric oxide (NO). We hypothesized that NO enhances the TNF-α-induced death of retinal neurons through a suppression of nuclear factor-κB (NF-κB) by nitrosylation. In this study, cells from the RGC-5 line were exposed to different concentrations (2.0, 10, and 50 ng/ml) of TNF-α, and the degree of TNF-α-induced cell death was determined by the WST-8 assay and by flow cytometric measurements of the externalization of phosphatidylserine. The effects of etanercept, a soluble TNFR-Fc fusion protein, and S-nitroso-N-penicillamine (SNAP), an NO donor, on the toxicity were determined. Experiments were also performed to determine whether nitric oxide synthase (NOS) was associated with the toxicity of TNF-α. The activation of NF-κB was determined by the detection of the p65 subunit in the nuclear extracts. Our results showed that exposure of RGC-5 cells to different concentrations of TNF-α significantly decreased the number of living cells in a dose-dependent way. The death was partially due to apoptosis with an externalization of phosphatidylserine, and the death was suppressed by etanercept. Exposure to TNF-α increased the activation of NF-κB and the expression of iNOS. Although NF-κB inhibitors suppressed the increase of iNOS, they also potentiated the TNF-α-induced death. Both L-NAME and aminoguanidine, both NOS inhibitors, rescued the cells from death. In contrast, addition of SNAP caused nitrosylation of the inhibitory κB kinase, and suppressed the NF-κB activation and potentiated the TNF-α-induced neurotoxicity. These results indicate that NO potentiates the neurotoxicity of TNF-α by suppressing NF-κB.
Cellular and Molecular Neurobiology 07/2011; 32(1):95-106. · 2.29 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tissue kallikrein, a widely used vasodilator for the treatment of hypertension and peripheral circulatory disorder, acts by releasing kinin, a potent vasodilator peptide. To identify the role of tissue kallikrein in retinal neovascularization, we investigated the antiangiogenic effect by using an in vitro and in vivo angiogenesis model.
Tissue kallikrein in vitreous fluid was markedly elevated in proliferative diabetic retinopathy patients compared with that in control patients with macular hole and epiretinal membrane. Tissue kallikrein inhibited vascular endothelial growth factor-165 (VEGF165)-induced tube formation, proliferation, and migration in vitro angiogenesis model via suppression of the VEGF165-induced phosphorylation of VEGF receptor-2. Furthermore, tissue kallikrein cleavage of VEGF165 was on the C-terminal side, which was analyzed by Western blotting and mass spectrometry. When administered subcutaneously, tissue kallikrein reduced the pathological vascular changes in retinal neovascularization induced in neonatal mice by returning the retina to normoxia after exposure to hyperoxia.
These findings indicate that tissue kallikrein is partly involved in pathogenesis of proliferative diabetic retinopathy and may be a promising therapeutic agent that could cleave VEGF165 itself when administered by a peripheral route.