Brian C. Oveson

Increased expression of catalase and superoxide dismutase 2 reduces cone cell death in retinitis pigmentosa

Oxidative and nitrosative damage are major contributors to cone cell death in retinitis pigmentosa (RP). In this study, we explored the effects of augmenting components of the endogenous antioxidant defense system in models of RP, rd1, and rd10 mice. Unexpectedly, overexpression of superoxide dismutase 1 (SOD1) in rd1 mice increased oxidative damage and accelerated cone cell death. With an elaborate mating scheme, genetically engineered rd10 mice with either inducible expression of SOD2, Catalase, or both in photoreceptor mitochondria were generated. Littermates with the same genetic background that did not have increased expression of SOD2 nor Catalase provided ideal controls. Coexpression of SOD2 and Catalase, but not either alone, significantly reduced oxidative damage in the retinas of postnatal day (P) 50 rd10 mice as measured by protein carbonyl content. Cone density was significantly greater in P50 rd10 mice with coexpression of SOD2 and Catalase together than rd10 mice that expressed SOD2 or Catalase alone, or expressed neither. Coexpression of SOD2 and Catalase in rd10 mice did not slow rod cell death. These data support the concept of bolstering the endogenous antioxidant defense system as a gene-based treatment strategy for RP, and also indicate that coexpression of multiple components may be needed.

NADPH Oxidase Plays a Central Role in Cone Cell Death in Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a collection of diseases in which rod photoreceptors die from a variety of mutations. After rods die, the level of tissue oxygen in the outer retina becomes elevated and there is progressive oxidative damage to cones that ultimately triggers apoptosis. In this study, we investigated the hypothesis that NADPH oxidase (Nox) and/or xanthine oxidase serve as critical intermediaries between increased tissue oxygen and the generation of excessive reactive oxygen species that cause oxidative damage to cones. Apocynin, a blocker of Nox, but not allopurinol, a blocker of xanthine oxidase, markedly reduced the superoxide radicals visualized by hydroethidine in the outer retina in the retinal degeneration‐1 (rd1+/+) model of RP. Compared to rd1+/+ mice treated with vehicle, those treated with apocynin, but not those treated with allopurinol, had significantly less oxidative damage in the retina measured by ELISA for carbonyl adducts. Apocynin‐treated, but not allopurinol‐treated, rd1+/+ mice had preservation of cone cell density, increased mRNA levels for m‐ and s‐cone opsin, and increased mean photopic b‐wave amplitude. In Q344ter mice, a model of dominant RP in which mutant rhodopsin is expressed, apocynin treatment preserved photopic electroretinogram b‐wave amplitude compared to vehicle‐treated controls. These data indicate that Nox, but not xanthine oxidase, plays a critical role in generation of the oxidative stress that leads to cone cell death in RP and inhibition of Nox provides a new treatment strategy.

N-acetylcysteine promotes long-term survival of cones in a model of retinitis pigmentosa

Retinitis pigmentosa (RP) is a major source of blindness caused by a large variety of mutations that lead to the death of rod photoreceptors. After rods die, cones gradually die from progressive oxidative damage. Several types of antioxidant formulations have been shown to reduce cone cell death over a relatively short‐time frame, but in order for this strategy to be translated into a new treatment for patients with RP, prolonged effects will be needed. In this study, we determined that orally administered N‐acetylcysteine (NAC) reduced cone cell death and preserved cone function by reducing oxidative damage in two models of RP, rd1+/+ and rd10+/+ mice. In rd10+/+ mice, supplementation of drinking water with NAC promoted partial maintenance of cone structure and function for at least 6 months. Topical application of NAC to the cornea also reduced superoxide radicals in the retina and promoted survival and functioning of cones. Since oral and/or topical administration of NAC is feasible for long‐term treatment in humans, and NAC has a good safety profile, it is reasonable to consider clinical trials to evaluate the effects of prolonged treatment with NAC in patients with RP. J. Cell. Physiol. 226: 1843–1849, 2011.

Sustained delivery of a HIF-1 antagonist for ocular neovascularization.

Doxorubicin (DXR) and daunorubicin (DNR) inhibit hypoxia-inducible factor-1 (HIF-1) transcriptional activity by blocking its binding to DNA. Intraocular injections of DXR or DNR suppressed choroidal and retinal neovascularization (NV), but also perturbed retinal function as demonstrated by electroretinograms (ERGs). DXR was conjugated to novel copolymers of branched polyethylene glycol and poly(sebacic acid) (DXR-PSA-PEG3) and formulated into nanoparticles that when placed in aqueous buffer, slowly released small DXR-conjugates. Intraocular injection of DXR-PSA-PEG3 nanoparticles (1 or 10 μg DXR content) reduced HIF-1-responsive gene products, strongly suppressed choroidal and retinal NV, and did not cause retinal toxicity. In transgenic mice that express VEGF in photoreceptors, intraocular injection of DXR-PSA-PEG3 nanoparticles (10 μg DXR content) suppressed NV for at least 35 days. Intraocular injection of DXR-PSA-PEG3 nanoparticles (2.7 mg DXR content) in rabbits resulted in sustained DXR-conjugate release with detectable levels in aqueous humor and vitreous for at least 105 days. This study demonstrates a novel HIF-1-inhibitor-polymer conjugate formulated into controlled-release particles that maximizes efficacy and duration of activity, minimizes toxicity, and provides a promising new chemical entity for treatment of ocular NV.

Hydrophobic versus double-square-edged hydrophilic foldable acrylic intraocular lens: effect on posterior capsule opacification.

PURPOSE: To evaluate posterior capsule opacification (PCO) 2 years after cataract surgery with implantation of a hydrophobic acrylic or single‐piece sharp‐edged hydrophilic acrylic intraocular lens (IOL). SETTING: Toyama Prefectural Central Hospital, Toyama, Japan. DESIGN: Case‐control study. METHODS: Patients with bilateral senile cataract were prospectively randomized to receive a hydrophobic IOL (Acrysof SA60AT) in 1 eye and a hydrophilic IOL (Meridian HP60M) in the other eye. The PCO density value, degree of IOL decentration and tilt, and anterior chamber depth (ACD) were measured using Scheimpflug videophotography 1, 6, 12, 18, and 24 months after surgery. Visual acuity and the number of eyes requiring neodymium:YAG laser capsulotomy were also assessed. RESULTS: The study evaluated 16 eyes (63 patients). The PCO value in the hydrophilic group increased significantly with time and was statistically significantly greater than in the hydrophobic group 18 and 24 months postoperatively (both P<.001). The capsulotomy rate was statistically significantly higher in the hydrophilic group than in the hydrophobic group (P<.01). Visual acuity in the hydrophilic group worsened significantly with time and was statistically significantly worse than in the hydrophobic group at 18 and 24 months (both P<.001). Intraocular lens decentration, IOL tilt, and the ACD did not change significantly during the follow‐up in either group (P>.05), and there were no statistically significant postoperative differences in these parameters between the 2 IOL groups (P>.05). CONCLUSION: Two years after surgery, the hydrophobic IOL group had less PCO, a lower capsulotomy rate, and better visual acuity than the hydrophilic IOL group. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.

Topical Pazopanib Blocks VEGF-Induced Vascular Leakage and Neovascularization in the Mouse Retina but Is Ineffective in the Rabbit

PURPOSEnTo test the effect of pazopanib, a tyrosine kinase inhibitor that blocks VEGF and platelet-derived growth factor (PDGF) receptors and c-Kit, on vascular leakage and neovascularization (NV) in the retina.nnnMETHODSnPazopanib was tested to determine its effect on VEGF-induced vascular permeability via measurement of [(3)H]mannitol retina to lung (RLLR) and retina to renal leakage ratios (RRLR) and in rho/VEGF mice with subretinal NV. In rabbits, the effect of intravitreal, topical, and systemic pazopanib on VEGF-induced leakage was tested by vitreous fluorophotometry.nnnRESULTSnIn mice, oral pazopanib (40 mg/kg twice a day [bid]) reduced RLLR (0.84 to 0.58, P = 0.0014) and RRLR (0.55 to 0.30, P = 0.0018) in VEGF-injected eyes. After intraocular injection of VEGF into both eyes, topical pazopanib (10 mg/mL three times a day [tid] for 14 days) reduced RLLR (0.85 vs. 0.56, P = 0.001), RRLR (0.44 vs. 0.28, P = 0.0075), and immunoreactive albumin in the retina compared to values in fellow eye controls. Treatment of one eye of rho/VEGF mice with 10 mg/mL, but not 5 mg/mL, pazopanib tid reduced the mean area of subretinal NV compared to that in fellow eyes (0.0055 vs. 0.0025 mm(2), P = 0.020). In rabbits, intravitreal pazopanib suppressed VEGF-induced fluorescein leakage, but topical (10 mg/mL four times a day [qid] or 12 mg/mL bid) had no significant effect. Systemic administration of pazopanib by osmotic pump with or without 10 mg/mL drops tid also failed to suppress VEGF-induced leakage.nnnCONCLUSIONSnAdministration of pazopanib topically or systemically suppressed retinal vascular leakage in mice, but not rabbits. These data suggest differences in the blood-retinal barrier (BRB) of mice and rabbits and indicate that penetration through the outer BRB may be needed for topically administered drugs to exert effects in the retina.

Retinal detachment in morning glory syndrome with large hole in the excavated disc.

Purpose. To present a case of morning glory syndrome (MGS) associated with retinal detachment and to discuss the pathogenesis of retinal tear. Methods. A 2-year-old-girl had a MGS with a large hole in the excavated disc and retinal detachment. The visual acuity was 4/200 in the affected eye. The excavated disc and retinal detachment were con-firmed by echogram. Optical coherence tomography demonstrated that the large hole was connected to the subretinal space. The excavated lesion did not show contractions. The detachment area and the volume of subretinal fluid rose and fell between initial examinations, but ultimately increased. After 2 years of observations, surgery was performed as the retinal detachment had enlarged to include the macula. Results. Surgery included triamcinolone-assisted vitrectomy, subretinal fluid drainage through the large hole in the excavated disc, retinal photocoagulation along the excavated disc, and long-acting gas tamponade. One month later, the retina was redetached due to incomplete closure of the hole. A second operation was performed using silicone oil tamponade. Ultimately, the retina was reattached after silicone oil-fluid exchange surgery. Conclusions. One possible reason for a large hole in an excavated disc is origination of the tear from a congenital defect, such as an optic pit. The retinal detachment in patients with MGS with a large hole in the disc can be treated with triamcinolone-assisted pars plana vitrectomy and retinal photocoagulation along the excavated disc. This case has shown that one critical component for a high success rate is the tamponade agent used in the vitreous.

Optical coherence tomography findings in optic nerve pit maculopathy after vitrectomy.

PURPOSEnThe purpose of this study was to present a case of optic nerve pit maculopathy and reappraise the previous concepts regarding the pathways of the fluid and the development.nnnMETHODSnA 24-year-old man had an optic nerve pit maculopathy. The visual acuity was 20/50 in the affected eye. Optical coherence tomography showed a multilayered separation of the neurosensory retina, serous retinal detachment, and the optic nerve pit with no membrane on the optic nerve. After 2 months of observations, surgery was performed.nnnRESULTSnSurgery included vitrectomy, the separation of the posterior hyaloid, the internal limiting membrane peeling, and gas tamponade. No laser was performed. The vision improved to 20/20, and optical coherence tomography demonstrated that the inner retinal layer separation was resolved except for the ganglion cell layer connected to the optic nerve pit, and subretinal fluid was increased 1 month after surgery. Eventually, the retinal layer separation and the subretinal fluid were resolved completely.nnnCONCLUSIONSnVitrectomy with internal limiting membrane peeling and gas tamponade without any additional laser photocoagulation seems to be sufficient for the treatment. Our observations suggest that the fluid can move directly from the optic pit into multiple layers, and fluid emanating from the optic nerve pit still extended even after surgery.

Pigment inside the lens associated with lenticonus

A 23-year-old Japanese man reported having progressive visual decline in his left eye for several months. The visual acuity in that eye had been better than 20/25 at a health check 4 years previously. The patient had not had a thorough eye examination, including lens status, and had no prior ocular trauma. On examination, visual acuity was hand motion and a mature cataract was present. The family history was negative. Examination of the fellow eye and systemic test results were normal. Uneventful phacoemulsification and intraocular lens implantation in the capsular bagwere performed. The posterior capsule contained a lenticonus with pigmentation inside and surrounding it (Figure 1). The remnant hyaloid artery was not seen, and the fundus was normal. One week after

Long-term outcome after vitrectomy for macular edema with retinal vein occlusion dividing into the occlusion site.

Purpose. To investigate the efficacy of treatment for macular edema secondary to retinal vein occlusion (RVO) with vitrectomy. Methods. This retrospective study identified patients with macular edema associated with RVO between January 2004 and April 2006. Inclusion criteria were eyes with (1) preoperative visual acuity (VA) of 20/40 or worse, (2) a central foveal thickness (CFT) greater than 250u2009μm, and (3) vitrectomy with internal limiting membrane and intravitreal triamcinolone acetonide. Each patient had their RVO classified as a major or macular BRVO or hemispheric RVO (HSRVO). Results. Forty-six eyes with major BRVO, 18 eyes with macular BRVO, and 17 eyes with HSRVO were investigated. VA was significantly improved at 24 months after surgery for each group (P < 0.05). Vision in the macular BRVO group 24 months after surgery was significantly better than that in other groups (P < 0.05). For each group, a concomitant reduction of CFT was noted at every time point when compared to preoperative values (P < 0.001). Conclusions. In macular BRVO, the postoperative vision 24 months after surgery was significantly better than the other groups. These findings suggest that additional and earlier treatments might be more important for patients with major BRVO and HSRVO than for those with macular BRVO.