[Show abstract][Hide abstract] ABSTRACT: Whole exome sequencing (WES) is a powerful technique for identifying sequence changes in the human genome. The goal of this study was to delineate the genetic defects in patients with inherited retinal diseases (IRDs) using WES. WES was performed on 90 patient DNA samples from 68 families and 226 known genes for IRDs were analyzed. Sanger sequencing was used to validate potential pathogenic variants that were also subjected to segregation analysis in families. Thirty-three causative mutations (19 novel and 14 known) in 25 genes were identified in 33 of the 68 families. The vast majority of mutations (30 out of 33) have not been reported in the Israeli and the Palestinian populations. Nine out of the 33 mutations were detected in additional families from the same ethnic population, suggesting a founder effect. In two families, identified phenotypes were different from the previously reported clinical findings associated with the causative gene. This is the largest genetic analysis of IRDs in the Israeli and Palestinian populations to date. We also demonstrate that WES is a powerful tool for rapid analysis of known disease genes in large patient cohorts.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the long-term outcome of bevacizumab therapy for neovascular age related macular degeneration (NVAMD) in the setting of a clinic.
Consecutive group of NVAMD patients who were treated in a single 3(rd) referral center with bevacizumab using a loading dosage of 3 monthly injections followed by variable dosing for at least 48 months were retrospectively evaluated. Genotyping was performed for CFH (rs1061170), HTRA1 (rs1200638), and C3 (rs2230199). Main outcome measures included functional and morphological treatment outcomes as well as their risk allele associations.
Out of 128 patients who started bevacizumab treatment over 4 years before the study endpoint [mean (±SD): 60 ± 10.9 months], 75 eyes of 67 (52.3%) patients, were still followed. Mean best corrected visual acuity (BCVA) (LogMAR ± SEM) improved from 0.66 ± 0.07 at baseline to 0.48 ± 0.05 (p = 0.012) at 1 year, but deteriorated from the 3(rd) year on and at the final exam reduced to 0.69 ± 0.07 (p = 0.6, compared with initial BCVA). Macular thickness mirrored visual acuity (VA) changes showing initial thinning followed by thickening from the 3(rd) year on. Individuals carrying the CFH risk -allele had a mean thickening (microns ± SEM) of 66.9 ± 70.4 versus a mean thinning of 76.8 ± 22 in non-carriers (p = 0.015).
Bevacizumab therapy for NVAMD using a flexible treatment algorithm in a "real life" clinical setting initially obtained VA gain and thinning of the macula that were maintained for two years, but were lost later on.
[Show abstract][Hide abstract] ABSTRACT: Adult-onset foveomacular vitelliform dystrophy (AFVD) was first described by Gass four decades ago. AFVD is characterized by subretinal vitelliform macular lesions and is usually diagnosed after the age of 40 years. The lesions gradually increase and then decrease in size over the years, leaving an area of atrophic outer retina and retinal pigment epithelium. This process is accompanied by a loss of visual acuity. Vitelliform lesions manifest as autoflourescence and initially have a dome-shape subretinal appearance on optical coherence tomography. Electro-oculogram and full-field electroretinogram finding are typically normal. A similar phenotype is also associated with systemic disorders such as cancer, drug toxicity, and mitochondrial diseases. Phenocopies are also associated with ocular disorders, including vitreomacular traction, age-related macular degeneration, pseudodrusen, and central serous choroidopathy. A minority of AFVD patients have a mutation in the PRPH2, BEST1, IMPG1, or IMPG2 genes. A single-nucleotide polymorphism in the HTRA1 gene has also been associated with this phenotype. Accordingly, the phenotype can arise from alterations in the photoreceptors, retinal pigment epithelium, and/or interphotoreceptor matrix. Excess outer segment production and/or impaired outer segment uptake due to impaired phagocytosis are the likely underlying mechanisms. At present, no cure is available for AFVD. Thus, the current challenges in the field include identifying the underlying cause in the majority of AFVD cases and the development of effective therapeutic approaches.
Progress in Retinal and Eye Research 02/2015; 47. DOI:10.1016/j.preteyeres.2015.02.001 · 8.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Bevacizumab and ranibizumab are routinely used to treat diabetic macular edema (DME). We aim to evaluate the usefulness of switching to ranibizumab therapy following bevacizumab treatment failure in eyes with DME.
We performed a retrospective analysis of a consecutive group of patients with DME who received ranibizumab injections following the failure of bevacizumab injections. The injections were delivered following a pro re nata protocol every 4-6 weeks. The data collected included demographics, systemic and ophthalmic findings, as well as the central subfield thickness according to spectral-domain OCT.
Eight eyes (5 patients) were included in the study. The median number of bevacizumab injections prior to the switch to ranibizumab was 4, and the median number of ranibizumab injections during the study was 2. The mean follow-up period was 541 ± 258 days. The mean central retinal thickness (CRT) (±SEM) was 539 ± 75 μm before the initiation of bevacizumab treatment, and 524 ± 43 μm after the last bevacizumab injection (p = 0.7). It reduced to 325 ± 26 μm following the ranibizumab injections (p = 0.0063). The best-corrected visual acuity (BCVA) improved in 4 eyes and remained stable in 4 eyes following the ranibizumab injections.
A ranibizumab therapy was effective in reducing the CRT in eyes that failed bevacizumab therapy. A BCVA improvement can also occur in these eyes. Switching between anti-vascular endothelial growth factor compounds may be beneficial in eyes with DME.
Case Reports in Ophthalmology 02/2015; 6(1):44-50. DOI:10.1159/000375230
[Show abstract][Hide abstract] ABSTRACT: Eye is the official journal of the Royal College of Ophthalmologists. It aims to provide the practising ophthalmologist with information on the latest clinical and laboratory-based research.
[Show abstract][Hide abstract] ABSTRACT: AimsAnti-vascular endothelial growth factor compounds are routinely used for the treatment of diabetic macular edema (DME). We aim to evaluate for the existence and magnitude of treatment effect on fellow un-injected eyes.MethodsA consecutive group of patients with bilateral DME who received unilateral bevacizumab injections was retrospectively evaluated. Data collected included demographics, ophthalmic and systemic findings, and optical coherence tomography (OCT) measurements of macular thickness.ResultsThirty-five patients were evaluated. Mean follow-up was 245 days (range: 30-800), and the mean number of bevacizumab injections was 3.6 (range: 1-11). At end of follow-up, the mean (SD) OCT central subfield thickness reduced by 72±112 micron in the injected eye (from 469±139 to 397±120 micron; P=0.001), while in the non-injected eye it reduced by 49±75 micron (from 380±130 to 331±106 micron; P<0.001). Sixteen injected eyes (45.7%) showed central subfield thickness reduction of ≥50 micron while 10 (28.6%) non-injected eyes showed such thickness reduction. Improved VA following treatment was detected in 14 (40%) injected eyes and in 15 (43%) non-injected eyes.Conclusions
Unilateral bevacizumab injections in patients with bilateral DME are often associated with bilateral response.Summary StatementAnti-vascular endothelial growth factor compounds are routinely used for the treatment of diabetic macular edema (DME). In this retrospective study, we show that unilateral bevacizumab injections often result in reduction of the macular thickness in the fellow un-injected eye.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To evaluate choroidal neovascularization (CNV) associated with adult-onset foveomacular vitelliform dystrophy (AOFVD) and its response to bevacizumab therapy.
Demographics, clinical characteristics, response to bevacizumab therapy, and central foveal thickness (CFT) were retrospectively assessed in 11 eyes with CNV associated with AOFVD. Sixty consecutive patients with neovascular age-related macular degeneration (AMD) were compared to the patients with AOFVD for all clinical characteristics and responses evaluated.
The mean (±SD) initial logMAR visual acuity (0.7 ± 0.8 vs. 1 ± 0.75), age at onset, number of bevacizumab injections (12.4 ± 10.4 vs 9 ± 6.7), and final logMAR visual acuity (0.87 ± 0.7 vs 1 ± 0.85) were similar between AOFVD and AMD. The mean CFT in AOFVD was reduced from 418 ± 144 µm to 330 ± 64 µm following treatment (p = 0.03). At the final examination, visual acuity had improved in 3 eyes, stabilized in 1 eye, and was reduced in 7 of the AOFVD eyes examined.
Bevacizumab therapy for AOFVD-associated CNV resulted in reduced foveal thickness, but a guarded visual outcome was still found, due to progression of the vitelliform lesions.
European journal of ophthalmology 05/2014; 24(6). DOI:10.5301/ejo.5000486 · 1.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: White blood cells, particularly monocytes and their descendants, macrophages, have been implicated in age-related macular degeneration (AMD) pathology. In this minireview, we describe the current knowledge of monocyte and macrophage involvement in AMD. Chemokine receptors present on these cells such as CCR1, CCR2, and CX3CR1, and their roles in monocyte/macrophage recruitment to sites of injury and inflammation in the context of AMD will be reviewed. Mice models for perturbation of chemokine receptors that recapitulate some of the features of AMD are also described. The body of evidence from human and rodent studies at this point in time suggests that monocyte and macrophages may modulate the course of AMD.
Advances in Experimental Medicine and Biology 03/2014; 801:199-205. DOI:10.1007/978-1-4614-3209-8_26 · 1.96 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Oxidative injury is involved in retinal and macular degeneration. We aim to assess if retinal degeneration associated with genetic defect modulates the retinal threshold for encountering additional oxidative challenges.
Retinal oxidative injury was induced in degenerating retinas (rd10) and in control mice (WT) by intravitreal injections of paraquat (PQ). Retinal function and structure was evaluated by electroretinogram (ERG) and histology, respectively. Oxidative injury was assessed by immunohistochemistry for 4-Hydroxy-2-nonenal (HNE), and by Thiobarbituric Acid Reactive Substances (TBARS) and protein carbonyl content (PCC) assays. Anti-oxidant mechanism was assessed by quantitative real time PCR (QPCR) for mRNA of antioxidant genes and genes related to iron metabolism, and by catalase activity assay.
Three days following PQ injections (1 µl of 0.25, 0.75, and 2 mM) the average ERG amplitudes decreased more in the WT mice compared with the rd10 mice. For example, following 2 mM PQ injection, ERG amplitudes reduced 1.84-fold more in WT compared with rd10 mice (p = 0.02). Injection of 4 mM PQ resulted in retinal destruction. Altered retina morphology associated with PQ was substantially more severe in WT eyes compared with rd10 eyes. Oxidative injury according to HNE staining and TBARS assay increased 1.3-fold and 2.1-fold more, respectively, in WT compared with rd10 mice. At baseline, prior to PQ injection, mRNA levels of antioxidant genes (Superoxide Dismutase1, Glutathione Peroxidase1, Catalase) and of Transferrin measured by quantitative PCR were 2.1-7.8-fold higher in rd10 compared with WT mice (p<0.01 each), and catalase activity was 1.7-fold higher in rd10 (p = 0.0006).
This data suggests that degenerating rd10 retinas encounter a relatively lower degree of damage in response to oxidative injury compared with normal retinas. Constitutive up-regulation of the oxidative defense mechanism in degenerating retinas may confer such relative protection from oxidative injury.
PLoS ONE 02/2014; 9(2):e87751. DOI:10.1371/journal.pone.0087751 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Retinal detachment can develop following brachytherapy for uveal melanoma. This complication may result in substantial visual loss and poses a significant therapeutic dilemma due to the required surgical intervention for correction of the detachment. We report the incidence of retinal detachment in eyes treated with brachytherapy for posterior uveal melanoma and the outcome of pars plana vitrectomy in those eyes.
Patients who developed tractional or combined tractional-rhegmatogenous retinal detachment following brachytherapy for posterior uveal melanoma in a single referral centre were retrospectively evaluated. Clinical findings, demographics, and ophthalmic imaging findings were recorded, as well as the manner of treatment and its success.
Seven of the 473 posterior uveal melanoma patients (1.48%), who were treated between 2000 and 2011 with brachytherapy, developed tractional or combined tractional-rhegmatogenous retinal detachment. Retinal detachment developed at a mean of 50.1 months (range 3.5-120 months) following brachytherapy. All patients underwent pars plana vitrectomy. Retinas remained attached in each of the cases. In five of seven patients there was substantial improvement in visual acuity following repair of the retinal detachment. No tumour growth or dissemination were observed during the mean follow-up of 18.4 months after vitrectomy (range 10-36 months).
Tractional and tractional-rhegmatogenous retinal detachment are rare complications of treated uveal melanoma. Pars plana vitrectomy appears to be an effective and safe procedure in such cases.
The British journal of ophthalmology 09/2013; 98(4). DOI:10.1136/bjophthalmol-2013-303331 · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pathologic angiogenesis mediated by abnormally polarized macrophages plays a central role in common age-associated diseases such as atherosclerosis, cancer, and macular degeneration. Here we demonstrate that abnormal polarization in older macrophages is caused by programmatic changes that lead to reduced expression of ATP binding cassette transporter ABCA1. Downregulation of ABCA1 by microRNA-33 impairs the ability of macrophages to effectively efflux intracellular cholesterol, which in turn leads to higher levels of free cholesterol within senescent macrophages. Elevated intracellular lipid polarizes older macrophages to an abnormal, alternatively activated phenotype that promotes pathologic vascular proliferation. Mice deficient for Abca1, but not Abcg1, demonstrate an accelerated aging phenotype, whereas restoration of cholesterol efflux using LXR agonists or miR-33 inhibitors reverses it. Monocytes from older humans with age-related macular degeneration showed similar changes. These findings provide an avenue for therapeutic modulation of macrophage function in common age-related diseases.
[Show abstract][Hide abstract] ABSTRACT: Age-related macular degeneration (AMD) is a common cause of blindness in older individuals. To accelerate the understanding of AMD biology and help design new therapies, we executed a collaborative genome-wide association study, including >17,100 advanced AMD cases and >60,000 controls of European and Asian ancestry. We identified 19 loci associated at P < 5 × 10-8. These loci show enrichment for genes involved in the regulation of complement activity, lipid metabolism, extracellular matrix remodeling and angiogenesis. Our results include seven loci with associations reaching P < 5 × 10-8 for the first time, near the genes COL8A1-FILIP1L, IER3-DDR1, SLC16A8, TGFBR1, RAD51B, ADAMTS9 and B3GALTL. A genetic risk score combining SNP genotypes from all loci showed similar ability to distinguish cases and controls in all samples examined. Our findings provide new directions for biological, genetic and therapeutic studies of AMD.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
We evaluated the role of Crumbs homolog 1 (CRB1) in autosomal recessive (AR) retinal diseases in the Israeli and Palestinian populations using homozygosity mapping.
Clinical analysis included family history, ocular examination, full-field electroretinography (ERG), and funduscopy. Molecular analysis included homozygosity mapping using whole genome single nucleotide polymorphism (SNP) arrays and mutation analysis of CRB1.
We recruited over 400 families with AR nonsyndromic retinal degenerations, including retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). SNP array analysis was performed on 175 index cases, eight of whom carried a homozygous region on chromosome 1 harboring CRB1. A subsequent CRB1 mutation analysis of the eight families, followed by screening of candidate founder mutations in the whole cohort of patients, revealed a total of 13 mutations, six of which are novel, in 15 families. Nine mutations were family-specific, and four were founder mutations identified in patients of Arab-Muslim origin, and Jews originated from Iraq and Kurdistan. Interestingly, a null mutation on at least one of the two mutated CRB1 alleles results in the LCA diagnosis, whereas patients carrying missense mutations were diagnosed with either RP or LCA. The average age at which CRB1 patients were referred to ERG testing was young (11 years). Of the 30 identified CRB1 patients, five had Coats-like exudative vasculopathy.
Our data show that CRB1 mutations are a relatively frequent cause of AR early-onset retinal degeneration in the Israeli and Palestinian populations (10% of LCA families), and causes severe retinal degeneration at an early age.
[Show abstract][Hide abstract] ABSTRACT: To evaluate if adult-onset foveomacular vitelliform dystrophy (AOFVD) and butterfly-shaped pigment dystrophy (BSPD) are associated with risk single-nucleotide polymorphisms (SNPs) for age-related macular degeneration (AMD).
This was a tertiary referral center-based cross-sectional study including 35 consecutive patients with BSPD and AOFVD, 317 patients with AMD, and 159 unaffected individuals. Demographics, clinical information, and ophthalmic imaging studies were collected. Sequencing was performed for the peripherin/RDS and BEST1 genes, and genotyping was performed for SNPs in the genes for complement factor H (CFH) (rs1061170), HTRA1 (rs11200638), and complement component 3 (C3) (rs2231099).
Adult-onset foveomacular vitelliform dystrophy and BSPD were diagnosed in 24 (68.6%) and 11 (31.4%) of the 35 patients, respectively. The mean (SD) age of patients with pattern dystrophy (PD) was 75.3 (10) years and median visual acuity was 0.7. Pattern dystrophy was associated with the HTRA1 risk allele compared with unaffected individuals (odds ratio, 1.72; 95% CI, 1.11-2.66; P = .03). The HTRA1 SNP showed similar prevalence in patients with AMD and PD. The CFH risk allele was significantly less common in patients with PD compared with patients with AMD (odds ratio, 0.47; 95% CI, 0.28-0.76; P = .002). No mutations in peripherin/RDS or BEST1 were detected.
The AOFVD and BSPD phenotypes are associated with an HTRA1 risk SNP. These phenotypes often present in elderly individuals who do not carry peripherin/RDS gene mutations and are associated with retinal pigment epithelium alterations and increased risk for choroidal neovascularization. Further research is required to evaluate if AOFVD and BSPD phenotypes in aged individuals are associated with AMD.
Archives of ophthalmology 08/2012; 130(8):987-91. DOI:10.1001/archophthalmol.2012.1483 · 4.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chemokine signaling and monocytes/macrophages were implicated in the pathogenesis of AMD. We tested the association between chemokines involved in monocyte recruitment and AMD.
Immunophenotyping for white blood cell (WBC) populations including CD14++CD16- and CD14+CD16+ monocytes, CD19+, CD3+, and CD16+ lymphocytes, and chemokine receptors CCR1, CCR2, CCR5, CX(3)CR1, and CXCR4 was performed on peripheral blood from treatment-naïve neovascular AMD (NV-AMD) patients and controls. The mRNA level of chemokine receptors in monocytes was measured with quantitative-PCR. Systemic levels of major chemokine ligands CCL2, CCL5, CCL3, and CXCL10 were evaluated by ELISA. Genotyping was performed for risk SNPs for AMD in the CFH, C3, and HTRA1 genes.
The percentage of WBC subpopulations tested was similar between NV-AMD patients (n = 18) and controls (n = 20). CD14+CD16+ monocyte subpopulation showed a 3.5-fold increased expression of CCR1 (P = 0.039; t-test) and a 2.2-fold increased expression of CCR2 (P = 0.027) in patients compared with controls. Increased CCR1 and CCR2 expression was correlated with each other in patients (R(2) = 0.64, P < 0.0001), but not controls (R(2) = 0.02, P = 0.57). Increased mRNA levels of CCR1 (1.6-fold, P = 0.037) and CCR2 (1.6-fold, P = 0.007) were found in monocytes from NV-AMD patients. Chemokine receptor expression was not correlated with the presence of risk SNPs, and was not associated with blood chemokine levels.
CCR1 and CCR2 are coupregulated on the CD14+CD16+ monocyte population in NV-AMD patients. These data implicate CD14+CD16+ monocytes and chemokine signaling in AMD. Additional investigation is needed to elucidate the role of these monocytes and their potential as a biomarker or therapeutic target for AMD.
[Show abstract][Hide abstract] ABSTRACT: Delayed diagnosis of choroidal neovas cularization (CNV) in age-related macular degeneration (AMD) adversely affects visual outcome.
To identify factors associated with early detection of CNV in the clinic setting.
Demographic and clinical data and lesion characteristics were retrospectively collected from 76 consecutive AMD patients who had a history of CNV in one eye and presented with CNV in the second eye. These data were evaluated for association with visual acuity (VA) at the time of presentation.
Better VA was associated with a history of CNV in the fellow eye (P < 0.0001), adherence to follow-up every 4 months (P = 0.015), younger age (P = 0.03), smaller lesion (P < 0.0001), and non-subfoveal location (P = 0.048). VA of the fellow eye did not correlate with VA at presentation with CNV.
These data suggest that patients' experience of CNV, regardless of VA, facilitates early diagnosis in the fellow eye. Adherence to follow-up in the routine clinic setting also facilitates early detection of CNV.
The Israel Medical Association journal: IMAJ 06/2012; 14(6):363-6. · 0.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A 66-year-old hypertensive woman complained of sudden loss of vision in her left eye. The clinical examination disclosed a
subhyaloid hemorrhage obscuring the fovea. Fluorescein angiography showed a hyperfluorescent spot under the hemorrhage, but
details were obscured. Indocyanine green videoangiography revealed a retinal arterial macroaneurysm as the cause of bleeding.
Indocyanine green videoangiography appears to be useful in the diagnosis of retinal arterial macroaneurysm obscured by preretinal
Annals of Ophthalmology 04/2012; 32(2):140-141. DOI:10.1007/s12009-000-0034-1 · 0.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Exposure of implanted episcleral element is a rare complication of buckling procedures. We describe a 40-year-old man who presented to our clinic complaining of foreign body sensation and irritation in his left eye which lasted several months. The patient history was positive for bilateral rhegmatogenous retinal detachment which was treated with sclera buckling. Upon presentation the left eye demonstrated phthisis and an exposed and infected sclera buckle and explant in the lower quadrants. The explant was removed, and the patient was treated with antibiotics. This case suggests that wide encircling sclera element might erode through the conjunctiva of eyes undergoing phthisis. Integrity of the conjunctiva overlying episcleral implant should be evaluated during routine follow-up exams to exclude exposure of the implant particularly in eyes undergoing phthisis.
[Show abstract][Hide abstract] ABSTRACT: The iron carrier transferrin is expressed at remarkably high levels in normal retinas and is upregulated during retinal degeneration. The authors characterized the consequences of genetically reduced retinal transferrin production on retinal structure and function.
Hypotransferrinemic (HPX⁻/⁻) mice treated with weekly intraperitoneal salvage transferrin injections were examined at 1 and 2 months of age. HPX⁻/⁻, HPX⁺/⁻, and wild-type (WT) mice were evaluated by electroretinography, ophthalmoscopy, and histology. Retinal iron content and transferrin levels were measured. RNA levels of genes involved in iron homeostasis and antioxidative response were determined by quantitative PCR. Oxidative injury was assessed by immunostaining for 4-hydroxy-2-nonenal (HNE).
At 2 months, dark-adapted, mixed rod-cone response b-wave amplitudes were significantly lower in HPX⁻/⁻ mice than in WT mice (340 ± 112 μV vs. 624 ± 134 μV [mean ± SEM]; P = 0.002). Oscillatory potentials were significantly suppressed in HPX mice, and ophthalmoscopy demonstrated marked retinal pallor. Quantitative immunostaining revealed a 39% reduction of transferrin content in HPX⁻/⁻ compared with WT retinas (P = 0.01). mRNA levels of Tf, Tf receptor, and ceruloplasmin were decreased, whereas mRNA for antioxidant genes were elevated in HPX⁻/⁻ retinas. HNE staining was reduced in mice carrying the mutant HPX allele. Histologic examination demonstrated preserved retinal structure, and retinal iron content was similar across the strains.
Despite the lack of wild-type retinal transferrin production and low levels of retinal transferrin protein, the retinal morphology and retinal iron content in HPX⁻/⁻ mice treated by systemic salvage transferrin injections are normal until age 2 months. However, retinal function and gene expression of some of the iron-associated genes are significantly altered.
[Show abstract][Hide abstract] ABSTRACT: Iron-associated oxidative injury plays a role in retinal degeneration such as age-related macular degeneration and retinitis pigmentosa. The metallo-complex zinc-desferrioxamine (Zn/DFO) may ameliorate such injury by chelation of labile iron in combination with release of zinc. We explored whether Zn/DFO can affect the course of retinal degeneration in the rd10 mouse model of retinitis pigmentosa. Zn/DFO-treated animals showed significantly higher electroretinographic responses at 3 and 4.5 weeks of age compared with saline-injected controls. Corresponding retinal (photoreceptor) structural rescue was observed by quantitative histological and immunohistochemical techniques. When administered alone, the components of the complex, Zn and DFO, showed a lesser, partial effect. TBARS, a marker of lipid peroxidation, and levels of oxidative DNA damage as quantified by 8-OHdG immunostaining were significantly lower in Zn/DFO-treated retinas compared with saline-injected controls. Reduced levels of retinal ferritin as well as reduced iron content within ferritin molecules were measured in Zn/DFO-treated retinas. The data, taken together, suggest that the protective effects of the Zn/DFO complex are mediated through modulation of iron bioavailability, leading to attenuation of oxidative injury. Reducing iron-associated oxidative stress using complexes such as Zn/DFO may serve as a "common pathway" therapeutic approach to attenuate injury in retinal degeneration.
Free Radical Biology and Medicine 07/2011; 51(8):1482-91. DOI:10.1016/j.freeradbiomed.2011.07.014 · 5.74 Impact Factor