sodium-iodate and Retinal-Degeneration

Animal models with pharmacologically induced retinal degeneration including sodium iodate (NaIO3) and N-methyl-N-nitrosourea (MNU) have been extensively used in ophthalmic research to investigate retinal degeneration. NaIO3 induces degeneration of the retinal pigment epithelium (RPE) followed by photoreceptor (PRC) cell death, mimicking features of age-related macular degeneration. In contrast, MNU leads to rapid destruction of the PRCs only, enabling the use of the MNU model to investigate degeneration induced in retinitis pigmentosa. It has been shown that multiple cell death pathways are involved in the cell-specific effects of the toxins. Necrosis has been identified as the cause of the NaIO3-induced RPE loss. PRC degeneration in the described models is mainly induced by programmed cell death, indicated by the upregulation of conventional apoptosis initiator and effector caspases. However, recent research points to the additional involvement of caspase-independent processes as endoplasmic reticulum stress and calpain activation. Since there is still a substantial amount of contradictory hypotheses concerning triggers of cell death, the use of pharmacological models is controversial. Thereby, the advantages of such models like the application reaching across species and strains as well as modulation of onset and severity of damage are not exploited to a full extent. Thus, the present review aims to give more insight into the involved cell death pathways and discusses recent findings in the most widely used retinal degeneration models. It might facilitate further studies aiming to develop putative therapeutic approaches for retinal degenerative diseases including combinatory treatment with cell death inhibitors and cell transplantation therapy.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Humans; Iodates; Iodoacetic Acid; Methylnitrosourea; Pharmaceutical Preparations; Photoreceptor Cells, Vertebrate; Retina; Retinal Degeneration; Retinal Pigment Epithelium

Age-related macular degeneration (AMD) is the leading cause of low vision and blindness for which there is currently no cure. Increased matrix metalloproteinase-9 (MMP-9) was found in AMD and potently contributes to its pathogenesis. Resident microglia also promote the processes of chronic neuroinflammation, accelerating the progression of AMD. The present study investigates the effects and mechanisms of the natural compound theissenolactone B (LB53), isolated from Theissenia cinerea, on the effects of RPE dysregulation and microglia hyperactivation and its retinal protective ability in a sodium iodate (NaIO

Topics: Animals; Disease Models, Animal; Humans; Lipopolysaccharides; Macular Degeneration; Matrix Metalloproteinase 9; Mice; Microglia; Retinal Degeneration; Retinal Pigment Epithelium; Retinal Pigments

It is important to explore the effective approaches to prevent dry age-related macular degeneration (AMD). In this study, significantly decreased full-field electroretinograms wave amplitudes and disordered retina structures were detected in rat retinas of sodium iodate induced dry AMD model. Six a- and b-wave amplitudes and the antioxidant activities were significantly increased, and the outer nuclear layer thickness was significantly improved in the rat retinas treated with the combination of Lactobacillus fermentum NS9 (LF) and aronia anthocyanidin extract (AAE) compared with the model. The effects were much better than the treatment with AAE alone. The proteomics analysis showed the expressions of α-, β- and γ-crystallins were increased by 3-8 folds in AAE treated alone and by 6-11 folds in AAE + LF treatment compared with the model, which was further confirmed by immuno-blotting analysis. Analysis of gut microbial composition indicated that higher abundance of the genus Parasutterella and species P. excrementihominis was found in the AAE + LF treatment compared with the other groups. The results indicated that the combined treatment of AAE + LF is a potential way to prevent the retina degeneration which is significantly better than the AAE treated alone.

Topics: Animals; Anthocyanins; Geographic Atrophy; Limosilactobacillus fermentum; Photinia; Plant Extracts; Rats; Retina; Retinal Degeneration

Sodium iodate (NaIO3) induces retinal pigment epithelium (RPE) dysfunction, which leads to photoreceptor degeneration. Previously, we used electron microscopy to show that the administration of NaIO3 resulted in the accumulation of cell debris in the subretinal space, which was thought to be caused by failed phagocytosis in the outer segment of the photoreceptor due to RPE dysfunction. We further analyzed the pathological changes in the retina and choroid of NaIO3-injected mice, and found that the expression of OTX2, an RPE marker, disappeared from central part of the RPE 1 day after NaIO3 administration. Furthermore, fenestrated capillaries (choriocapillaris, CC) adjacent to the RPE could not be identified only 2 days after NaIO3 administration. An examination of the expression of the CC-specific protein plasmalemma vesicle-associated protein (PLVAP), in sections and flat-mount retina/choroid specimens showed destruction of the CC, and complete disappearance of the PLVAP signal 7 days after NaIO3 administration. In contrast, CD31 flat-mount immunohistochemistry of the retina indicated no difference in retinal vessels between NaIO3-treated mice and controls. Electron microscopy showed that the fenestrated capillaries in the kidney and duodenum were morphologically indistinguishable between control and NaIO3-treated mice. We examined cytokine production in the retina and RPE, and found that the Vegfa transcript level in the RPE decreased starting 1 day after NaIO3 administration. Taken together, these observations show that NaIO3 reduces the CC in the early stages of the pathology, which is accompanied by a rapid decrease in Vegfa expression in the RPE.

Topics: Animals; Atrophy; Choroid; Down-Regulation; Iodates; Mice; Retinal Degeneration; Retinal Pigment Epithelium; Vascular Endothelial Growth Factor A

The lack of suitable animal models for (dry) age-related macular degeneration (AMD) has hampered therapeutic research into the disease, so far. In this study, pigmented rats and mice were systematically injected with various doses of sodium iodate (SI). After injection, the retinal structure and visual function were non-invasively characterized over time to obtain in-depth data on the suitability of these models for studying experimental therapies for retinal degenerative diseases, such as dry AMD.. SI was injected into the tail vein (i.v.) using a series of doses (0-70 mg/kg) in adolescent C57BL/6J mice and Brown Norway rats. The retinal structure and function were assessed non-invasively at baseline (day 1) and at several time points (1-3, 5, and 10-weeks) post-injection by scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT), and electroretinography (ERG).. After the SI injection, retinal degeneration in mice and rats yielded similar results. The lowest dose (10 mg/kg) resulted in non-detectable structural or functional effects. An injection with 20 mg/kg SI did not result in an evident retinal degeneration as judged from the OCT data. In contrast, the ERG responses were temporarily decreased but returned to baseline within two-weeks. Higher doses (30, 40, 50, and 70 mg/kg) resulted in moderate to severe structural RPE and retinal injury and decreased the ERG amplitudes, indicating visual impairment in both mice and rat strains.. After the SI injections, we observed dose-dependent structural and functional pathological effects on the retinal pigment epithelium (RPE) and retina in the pigmented mouse and rat strains that were used in this study. Similar effects were observed in both species. In particular, a dose of 30 mg/kg seems to be suitable for future studies on developing experimental therapies. These relatively easily induced non-inherited models may serve as useful tools for evaluating novel therapies for RPE-related retinal degenerations, such as AMD.

Topics: Animals; Disease Models, Animal; Electroretinography; Follow-Up Studies; Iodates; Macular Degeneration; Mice; Mice, Inbred C57BL; Rats; Retina; Retinal Degeneration; Retinal Pigment Epithelium; Sodium; Tomography, Optical Coherence

The degeneration of retinal neurons which occurs in many neurodegenerative diseases of retina such as retinitis pigmentosa and aged-related macular degeneration, is a progressive phenomenon and leads to permanent visual disability. Aside from their economic and social impact, those who suffer from these diseases have a poor quality of life due to the lack of cures. Researchers have turned to stem cell therapies as a potential solution to this global health crisis. Mesenchymal stem cells (MSCs) and their paracrine agents such as conditioned medium (CM) and exosomes (Exo) have been applied to treat different retinal disorders. This study compared the therapeutic effects of human adipose mesenchymal stem cells (hADSCs) and their secretome on an in vivo model of sodium iodate retinal neurodegeneration.. We analyzed the expression of retinal cells' specific mRNAs by RT-PCR and proteins by immunostaining as well as performing visual cliff avoidance test as a functional evaluation technique. There were four therapeutic groups in this study: hADSC, hADSC-CM, hADSC-Exo and hADSC-Exo + CM.. Although all groups showed different therapeutic effects on various retinal cells, the results of hADSC-CM were most striking, especially in terms of photoreceptor regeneration and retinal function.. The findings of present study demonstrated the different effects of MSC-based therapies on various retinal cells which could be helpful in designing more precise treatments that suit to each neurodegenerative disease mechanism and the cells involved. It also suggests that CM might be a better choice due to its multifactorial characteristic.

Topics: Aged; Animals; Culture Media, Conditioned; Humans; Iodates; Mesenchymal Stem Cells; Neurodegenerative Diseases; Quality of Life; Rats; Retinal Degeneration

Retinal pigment epithelium (RPE) degeneration is a leading cause of blindness in retinal degenerative diseases, but the mechanism of RPE regional degeneration remains largely unknown. This study aims to investigate the sensitivity of RPE to sodium iodate (SI) injury in the dorsal and ventral visual fields in mice and analyze whether overlaying cone photoreceptors regulate the sensitivity of RPE to SI-induced damage.. SI was used to induce RPE degeneration in mice. Hematoxylin-eosin staining, immunostaining, and TUNEL assay were used to evaluate retinal degeneration along the dorsal-ventral axis. Flat-mounted and sectional retinal immunostaining were used to analyze the distribution of cones along the dorsoventral axis in C57BL/6, albino, and 129 mice. Electroretinography was used to examine the retinal function.. Dorsal-central RPE was more sensitive to SI-mediated injury along the dorsal-ventral axis in C57BL/6 mice. Compared with the ventral RPE, the dorsal-central RPE was dominantly covered by M cone photoreceptors in these mice. Interestingly, M cone photoreceptor degeneration was followed by dorsal RPE degeneration under a low dose of SI. Furthermore, the sensitivity of dorsal RPE to a low dose of SI was reduced in both albino and 129 mouse strains with dominant mixed cones instead of M cones in the dorsal visual field.. These findings suggest that dorsal-central RPE is more sensitive to SI injury and that SI-induced RPE degeneration could be controlled by modifying the dominant overlying cone population in the mouse dorsal retina, thereby highlighting a potential role of M cones in RPE regional degeneration.

Topics: Animals; Disease Models, Animal; Iodates; Mice; Mice, Inbred C57BL; Retina; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Retinal Pigment Epithelium

Retinal degeneration (RD) is a group of serious blinding eye diseases characterized by photoreceptor cell apoptosis and progressive degeneration of retinal neurons. However, the underlying mechanism of its pathogenesis remains unclear.. In this study, retinal tissues from sodium iodate (NaIO. In total, 334 mRNAs, 77 long non-coding RNAs (lncRNAs), and 20 other RNA types were identified as differentially expressed in the retinas of NaIO. Overall, this study suggests that multiple chemokines participating in systemic inflammation may contribute to RD pathogenesis.

Topics: Animals; Chemokines; Gene Expression Profiling; Inflammation; Iodates; Rats; Retinal Degeneration; RNA, Messenger; Sequence Analysis, RNA

Dry age-related macular degeneration (dAMD) leads to serious burden of visual impairment and there is no definitive treatment. Previous studies have showed that naringenin (NAR) significantly increased electroretinography (ERG) c-wave in sodium iodate (NaIO. We tested the hypothesis that anti-oxidation mediated by Sirtuin 1 (SIRT1) was important to the protective effect of NAR on dAMD.. NaIO. NAR eye drops improved retinal function and morphology and normalized the protein expression of SIRT1 in mice exposed to NaIO. Our findings indicate that SIRT1-mediated anti-oxidation contributes to the protective effect of NAR eye drops on dAMD.

Topics: Animals; Carbazoles; Cell Line; Cell Survival; Female; Flavanones; Humans; Iodates; L-Lactate Dehydrogenase; Male; Mice; Ophthalmic Solutions; Protective Agents; Reactive Oxygen Species; Retinal Degeneration; Retinal Pigment Epithelium; Sirtuin 1; Up-Regulation

Different methods have been used to inject stem cells into the eye for research. We previously explored the intravitreal route. Here, we investigate the efficacy of intravenous and subretinal-transplanted human dental pulp stem cells (DPSCs) in rescuing the photoreceptors of a sodium iodate-induced retinal degeneration model.. Three groups of Sprague Dawley rats were used: intervention, vehicle group and negative control groups (n = 6 in each). Intravenous injection of 60 mg/kg sodium iodate (day 0) induced retinal degeneration. On day 4 post-injection of sodium iodate, the rats in the intervention group received intravenous DPSC and subretinal DPSC in the right eye; rats in the vehicle group received subretinal Hank's balance salt solution and intravenous normal saline; while negative control group received nothing. Electroretinogram (ERG) was performed to assess the retinal function at day 0 (baseline), day 4, day 11, day 18, day 26, and day 32. By the end of the study at day 32, the rats were euthanized, and both their enucleated eyes were sent for histology.. No significant difference in maximal ERG a-wave (p = 0.107) and b-wave, (p = 0.153) amplitude was seen amongst the experimental groups. However, photopic 30 Hz flicker amplitude of the study eye showed significant differences in the 3 groups (p = 0.032). Within the intervention group, there was an improvement in 30 Hz flicker ERG response of all 6 treated right eyes, which was injected with subretinal DPSC; while the 30 Hz flicker ERG of the non-treated left eyes remained flat. Histology showed improved outer nuclear layer thickness in intervention group; however, findings were not significant compared to the negative and vehicle groups.. Combination of subretinal and intravenous injection of DPSCs may have potential to rescue cone function from a NaIO

Topics: Animals; Dental Pulp; Disease Models, Animal; Humans; Iodates; Rats; Rats, Sprague-Dawley; Retinal Degeneration; Stem Cells

We developed and characterized a canine model of outer retinal degeneration induced by sodium iodate (SI) intravitreal injection after vitrectomy. In the preliminary study, we repeatedly injected SI intravitreally into the eyes of three canines to develop outer retinal degeneration two weeks after vitrectomy. Based on the preliminary study, a single dose of either 1.2 mg or 1.0 mg SI/0.05 mL was also injected (1.2 mg in n = 5 canines, 1.0 mg in n = 2 canines). Spectral domain-optical coherence tomography (OCT), electroretinography (ERG), and histological examinations were performed at baseline and following intravitreal injection. In the preliminary study, after a 0.5-mg SI injection and a 1.0-mg SI injection and after two 0.8-mg SI injections, retinal degeneration with retinal thinning was observed on OCT imaging. In the second study, after a single 1.0- or 1.2-mg SI injection, outer retinal degeneration was induced. All eyes showed diffuse outer retinal degeneration on OCT and a loss of both cone and rod responses in ERG. Histological examination also showed the loss of outer retinal layer. Intravitreally injected SI (1.0-1.2 mg) in a vitrectomized canine model induced outer retinal degeneration effectively, and could be evaluated through in vivo ophthalmic examination.

Topics: Animals; Disease Models, Animal; Dogs; Female; Humans; Intravitreal Injections; Iodates; Retina; Retinal Degeneration; Tomography, Optical Coherence; Vitrectomy

Epidemiological studies indicate that the daily intake of antioxidants from a traditional Asian diet reduces the risk of developing age-related macular degeneration. Many of the phytochemicals that are abundant in whole grains exhibit a wide variety of biological activity such as antioxidant, anti-inflammatory, and neuroprotective effects. Ferulic acid (FA) is a phenolic acid found in vegetables and grains that has therapeutic potential for diabetes mellitus, Alzheimer's disease, and other diseases. We investigated the retinal protective effect of FA in a sodium iodate (NaIO

Topics: Administration, Oral; Animals; Caffeic Acids; Cell Line; Cell Survival; Coumaric Acids; Electroretinography; Epithelial Cells; Humans; Hydrogen Peroxide; Iodates; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Protective Agents; Retina; Retinal Degeneration; Tomography, Optical Coherence

We verified whether fetal RPE (fRPE) cells and mesenchymal stem cells (MSCs) cotransplantation can combine the features of these two cell types and alleviate retinal degeneration in a retinal degenerative disease mouse model.. Tail vein injection of sodium iodate (NaIO3) was conducted to establish the retinal degenerative disease mouse model. MSCs and fRPE cells were transplanted either separately or combined in the subretinal space of retinal degenerative disease animals. ERG, optical coherence tomography, histologic, and immunofluorescence analyses were performed. Furthermore, the expression level of Crx, rhodopsin, Iba1, F4/80, Caspase 3, nerve growth factor, and brain-derived neurotrophic factor were assessed to investigate the mechanisms involved in cell transplantation effects.. Cotransplantation of fRPE and MSC cells promoted significant improvements in ERG results and in the survival rate of transplanted cells. In addition, MSC and fRPE cell cotransplantation resulted in an increase in the thickness of the total retina, as well as in the outer and inner nuclear layers. Combined transplantation also upregulated the expression level of Crx and rhodopsin and downregulated caspase 3 expression, highlighting its better photoreceptor rescue effect in relation to the single cell type transplantation. Finally, combined transplantation suppressed the expression of Iba1 and F4/80 factors while increasing the endogenous expression of nerve growth factor and brain-derived nerve growth factor neurotrophic factors. These data suggest that MSC and fRPE cell cotransplantation is able to suppress immunoreactions and promote neurotrophic factor excretion.. Combined transplantation of MSCs and fRPE cells results in a better retinal rescue effect than single cell type transplantation in NaIO3-induced retinopathy.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Electroretinography; Humans; Iodates; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Retinal Degeneration; Retinal Pigment Epithelium; Treatment Outcome

Topics: Animals; Capsicum; Cell Line; Fermentation; Glutathione; Humans; Iodates; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; RAW 264.7 Cells; Reactive Oxygen Species; Retina; Retinal Degeneration; Retinal Pigment Epithelium; Superoxide Dismutase

We sought to develop and characterize outer retinal degeneration induced by intravitreal injection of sodium iodate (SI) after vitrectomy in rabbits. To determine the effective dose of SI, the right eyes of 19 male New Zealand white rabbits received an intravitreal injection of SI or sham. Based on the dose-dependence results, 0.4 mg of SI in 0.05 mL of total volume was injected into the right eyes of 10 rabbits at two weeks after vitrectomy. In the dose-dependence study, localized retinal atrophy was observed with 0.3- and 0.4-mg SI injections without vitrectomy. Severe and diffuse retinal atrophy was identified by spectral-domain optical coherence tomography (SD-OCT) at one month after a 0.5-mg SI injection following vitrectomy. In the second experiment, 0.4 mg of SI in 0.05 mL was injected, and the severity of outer retinal degeneration was graded as one of two types according to electroretinography (ERG) response change. There was no response on ERG in complete retinal degeneration, 30% of all 10 rabbits. Intravitreal injection of 0.4 mg of SI into vitrectomized rabbit eyes induces diffuse outer retinal degeneration, and the degree of retinal degeneration can be evaluated through in vivo ophthalmic examination.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Electroretinography; Humans; Intravitreal Injections; Iodates; Rabbits; Retina; Retinal Degeneration; Tomography, Optical Coherence; Vitrectomy; Vitreous Body

Receptor interacting protein kinase 1 (RIPK1) plays a key role in necroptosis, which is a type of programmed necrosis that is involved in ocular diseases, including glaucoma and dry age-related macular degeneration (AMD). We previously introduced RIPK1-inhibitory compound (RIC), which has biochemical characteristics and a mode of action that are distinct from those of the prototype RIPK1 inhibitor necrostatin-1. The intraperitoneal administration of RIC exerts a protective effect on retinal ganglion cells against a glaucomatous insult. In this study, we examined the protective effect of RIC on retinal pigment epithelium (RPE) against sodium iodate (SI) insult, which is associated with dry AMD pathogenesis. The eye drop administration of RIC that reached on the retina prevented RPE loss in SI-induced retinal degeneration. RIC consistently demonstrated retinal protection in the funduscopy and electroretinogram analyses in SI-injected rabbits and iodoacetic acid-treated mini-pigs. Moreover, the in vivo protective effects of RIC were superior to those of ACU-4429 and doxycycline, which are other medications investigated in clinical trials for the treatment of dry AMD, and RIC did not induce retinal toxicity following topical administration in rats. Collectively, RIC displayed excellent retinal penetration and prevented retinal degeneration in the pathogenesis of dry AMD with a high in vivo efficacy.

Topics: Administration, Ophthalmic; Animals; Disease Models, Animal; Electroretinography; Geographic Atrophy; Iodates; Male; Ophthalmoscopy; Phenyl Ethers; Propanolamines; Protective Agents; Rabbits; Rats; Rats, Sprague-Dawley; Receptor-Interacting Protein Serine-Threonine Kinases; Retinal Degeneration; Retinal Ganglion Cells

Hydrogen possesses antioxidative effects and cures numerous types of ophthalmopathy, but the mechanism of hydrogen on ROS-induced retinal senescence remains elusive. In this study, retinal morphology revealed that hydrogen reduced the number and size of vitreous black deposits in Bruch's membrane in NaIO3 mice. Hydrogen also reduced ROS levels in the retina as assessed by DHE staining. Moreover, this result was consistent with the downregulation of expression of the oxidative stress hallmark OGG1. These findings suggested that hydrogen can reduce retinal oxidative stress induced by NaIO3, and this result was further verified using the antioxidant ALCAR. Mechanistic analysis revealed that hydrogen significantly inhibited the downregulation of Sirt3 expression, and this notion was confirmed using AICAR, which restores Sirt3 expression and activity. Moreover, hydrogen reduced the expression of p53, p21 and p16 and the number of blue-green precipitations in the retinas of NaIO3 mice as assessed by SA-β-gal staining. We also found that hydrogen decreased the expression of the DNA damage-related protein ATM, cyclinD1 and NF-κB but increased the expression of the DNA repair-related protein HMGB1, suggesting that hydrogen inhibits senescence in retinas of NaIO3 mice. Additionally, OCT examination revealed that hydrogen suppressed retinal high reflex formation significantly and prevented the retina from thinning. This result was supported by ERG assays that demonstrated that hydrogen prevented the reduction in a- and b-wave amplitude induced by NaIO3 in mice. Thus, our data suggest that hydrogen may inhibit retinal senescence by suppressing the downregulation of Sirt3 expression through reduced oxidative stress reactions.

Topics: Acetylcarnitine; Aging; Animals; Antioxidants; Ataxia Telangiectasia Mutated Proteins; Cyclin D1; DNA Damage; Gene Expression Regulation; HMGB1 Protein; Humans; Hydrogen; Iodates; Mice; Oxidative Stress; Reactive Oxygen Species; Retina; Retinal Degeneration; Sirtuin 3

Topics: Animals; Apoptosis; Dental Pulp; Disease Models, Animal; Electroretinography; Iodates; Male; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Photoreceptor Cells; Rats; Rats, Sprague-Dawley; Retinal Degeneration; Retinal Pigment Epithelium

As the world's population begins to age, retinal degeneration is an increasing problem, and various treatment modalities are being developed. However, there have been no therapies for degenerative retinal conditions that are not characterized by neovascularization. We investigated whether transplantation of mouse adipose tissue-derived stem cells (mADSC) into the intraperitoneal space has a rescue effect on NaIO

Topics: Adipose Tissue; Animals; Cells, Cultured; Ciliary Neurotrophic Factor; Disease Models, Animal; Injections, Intraperitoneal; Interleukin-6; Intravitreal Injections; Iodates; Lipopolysaccharides; Mice, Inbred C57BL; Protective Agents; Rats; Retinal Degeneration; Retinal Pigment Epithelium; RNA, Messenger; Stem Cell Transplantation; Stem Cells; Up-Regulation

In ophthalmological research, the use of zebrafish to investigate visual behaviors has been increasing, but can produce misleading, false-positive results if compounds adversely affect their motor functions or central nervous system. Therefore, histological analysis to identify a target organ is important in zebrafish toxicity assay. We investigated the retinal degeneration in zebrafish, using typical retinal toxicants, mainly sodium iodate and N-methyl-N-nitrosourea (MNU). No histopathological changes were found after sodium iodate exposure at 1.0 mM for 5 or 7 days in the retina of larval, juvenile, and adult zebrafish. There were also no obvious histopathological changes in the retina of adult zebrafish at 0.1 mM, even after 30 days treatment with sodium iodate. In addition, many proliferating cell nuclear antigen-positive cells were found not only in the ciliary marginal zone, but also in the outer nuclear layer, especially in larval and juvenile zebrafish with or without sodium iodate exposure. However, the concentrations of iodine in the blood and the eyeballs of adult zebrafish increased remarkably after the treatment. General retinal damage emerged after MNU exposure at 150 mg/l for 60 min in adult zebrafish, but first pyknotic cells appeared in the inner nuclear layer and the ganglion cell layer. Our findings indicate that zebrafish retina have a different reactivity pattern from mammalian animals against some retinal toxicants, and in them it is difficult to detect histopathological changes.

Topics: Animals; Disease Models, Animal; Iodates; Male; Proliferating Cell Nuclear Antigen; Rats, Sprague-Dawley; Retina; Retinal Degeneration; Species Specificity; Zebrafish

To determine the mechanism causing degeneration of the retinal pigment epithelium (RPE) and photoreceptors in mice after an intravenous injection of sodium iodate (NaIO3).. The time-dependent changes in NaIO3-induced retinal degeneration were determined by analyzing the retinal morphology by optical coherence tomographic (OCT) images, histological sections of the retina, physiology of the retina by electroretinography (ERG), and retinal blood flow by laser speckle flowgraphy. In addition, the expression of the genes associated with age-related macular degeneration in humans was assessed in the NaIO3-treated mice by RT-PCR. We also investigated whether macrophages were involved in the NaIO3-induced retinal degeneration.. The intravenous injection of 20 mg/kg NaIO3 altered the morphology of the RPE cells and the ERGs transiently. With 40 mg/kg of NaIO3, the degeneration of the RPE cells was still present at 28 days. Aggregated melanin granules were surrounded by zonula occludens protein 1 (ZO-1)-positive cells. In addition, 40 mg/kg of NaIO3 led to a reduction in the amplitudes of the a- and b-waves of the dark-adapted ERGs. Histological studies showed that macrophages had infiltrated the retina and were present around the altered RPE cells. Depletion of the macrophages by a prior injection of clodronate liposomes prevented the damage of the outer retina after the NaIO3 injection but not the RPE.. The NaIO3-induced retinal damage was reversible at low concentrations but permanent at high concentrations of NaIO3. The accumulation of macrophages around the RPE cells caused the photoreceptor cell death.

Topics: Animals; Apoptosis; Disease Models, Animal; Electroretinography; Fluorescein Angiography; In Situ Nick-End Labeling; Injections, Intravenous; Iodates; Laser-Doppler Flowmetry; Macrophages; Male; Mice; Mice, Inbred C57BL; Photoreceptor Cells, Vertebrate; Real-Time Polymerase Chain Reaction; Retinal Degeneration; Retinal Pigment Epithelium; Tomography, Optical Coherence

Animal models play critical roles in studies of the etiology and therapy of retinal degeneration (RD).. To establish an RD model without severe systemic side effects in monkeys.. Cynomolgus monkeys and Sprague-Dawley rats were treated with intravenous and intravitreal sodium iodate (SI). Electroretinographic (ERG) recording, fluorescein fundus angiography (FFA), optical coherence tomography (OCT) and a retinal morphology examination were conducted to evaluate retinal function and structure. ARPE-19 cells were treated with SI to assess cell viability and morphology. Glutathione (GSH) was administered to SI-treated cultured cells and rats for mechanistic studies.. Intravenous SI failed to induce RD in monkeys due to its lethal toxicity and the spontaneous recovery of visual function. However, intravitreal SI injection induced very rapid and severe retinal damage in both monkeys and rats. Different doses of SI were tested in both rats and monkeys, and the SI dose appropriate for the model was calculated. GSH partially rescued oxidative damage to SI-treated retinas. A combination of the appropriate dose of intravitreal SI and intravenous GSH generated moderate subacute RD.. An RD model was established in cynomolgus monkeys by intravitreal SI injection. The key advantages of this model are that lethal SI side effects can be avoided and that the structural and functional changes are similar to those in patients with RD, although the development of RD in the model is too rapid and more severe. An appropriate dose of SI plus systemic GSH generates delayed and moderate RD; this prolonged therapeutic window allows the development of new therapies, such as gene or stem cell-based therapy, for RD.

Topics: Animals; Disease Models, Animal; Electroretinography; Fluorescein Angiography; Humans; Intravitreal Injections; Iodates; Macaca fascicularis; Rats; Rats, Sprague-Dawley; Retinal Degeneration

To characterize the course of sodium iodate (SI)-induced retinal degeneration in young adult albino and pigmented mice.. Single intraperitoneal (IP) injections of SI (25, 50, and 100 mg/kg) were performed in 7- to 8-week-old BALB/c and C57Bl/6J mice. Retinal function and structure was assessed at baseline, 24 hours, 3 days, 1, 2, 3, and 4 weeks postinjection by optokinetic tracking response, ERG, optical coherence tomography (OCT), and histologic and immunohistochemical techniques.. The 50 mg/kg SI dosage was selected after dose ranging due to consistent retinal effects and lack of systemic toxicity. Time-dependent deterioration in retinal function and morphology was consistently observed between 1 and 4 weeks in all measured parameters. These include reduction of ERG responses, thinning of retinal layers as observed by OCT and histology, and loss of RPE nuclei. Immunohistochemistry revealed rapid RPE disorganization with loss of tight junctions and markedly reduced expression of RPE65 and rod opsin, accompanied by mislocalization of cone opsins. Earlier time points displayed variable results, including partial recovery of visual acuity at 1 week and supranormal ERG cone responses at 24 hours, suggesting possible limitations of early intervention and assessment in the SI model.. A single IP injection of 50 mg/kg SI leads to severe RPE injury followed by vision impairment, dysfunction, and loss of photoreceptors in both BALB/c and C57Bl/6J mice. This easily induced and reproducible noninherited model may serve as a useful tool for seeking and evaluating novel therapeutic modalities for the treatment of retinal degenerations caused by primary failure of the RPE.

Topics: Animals; Disease Progression; Dose-Response Relationship, Drug; Electroretinography; Iodates; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Retina; Retinal Degeneration; Tomography, Optical Coherence

We identify noninvasive biomarkers that measure the severity of oxidative stress within retina layers in sodium iodate (SI)-atrophy vulnerable (C57BL/6 [B6]) and SI-atrophy resistant (129S6/SvEvTac [S6]) mice.. At 24 hours after administering systemic SI to B6 and S6 mice we measured: (1) superoxide production in whole retina ex vivo, (2) excessive free radical production in vivo based on layer-specific 1/T1 values before and after α-lipoic acid (ALA) administration while the animal was inside the magnet (QUEnch-assiSTed MRI [QUEST MRI]), and (3) visual performance (optokinetic tracking) ± antioxidants; control mice were similarly assessed. Retinal layer spacing and thickness in vivo also were evaluated (optical coherence tomography, MRI).. SI-treated B6 mice retina had a significantly higher superoxide production than SI-treated S6 mice. ALA-injected SI-treated B6 mice had reduced 1/T1 in more retinal layers in vivo than in SI-treated S6 mice. Uninjected and saline-injected SI-treated B6 mice had similar transretinal 1/T1 profiles. Notably, the inner segment layer 1/T1 of SI-treated B6 mice was responsive to ALA but was unresponsive in SI-treated S6 mice. In both SI-treated strains, antioxidants improved contrast sensitivity to similar extents; antioxidants did not change acuity in either group. Retinal thicknesses were normal in both SI-treated strains at 24 hours after treatment.. QUEST MRI uniquely measured severity of excessive free radical production within retinal layers of the same subject. Identifying the mechanisms underlying genetic vulnerabilities to oxidative stress is expected to help in understanding the pathogenesis of retinal degeneration.

Topics: Analysis of Variance; Animals; Antioxidants; Biomarkers; Contrast Sensitivity; Free Radicals; Iodates; Magnetic Resonance Imaging; Mice; Mice, Inbred C57BL; Oxidative Stress; Retinal Degeneration; Superoxides; Visual Acuity

Our purpose was to evaluate the anatomical and functional changes in retinae of rabbit eyes following monocular intravitreal injection of sodium iodate (SI).. Twenty albino rabbits were divided into four groups and underwent monocular intravitreal injection with four different doses of SI (0.1, 0.2, 0.4, and 0.8 mg). Before and for 28 days after injection, the eyes were examined using fundus photography, optical coherence tomography (OCT), and electroretinography (ERG). At postinjection days 2, 7, and 28, the eyes were enucleated and underwent histological examination.. On fundus examination, no distinct retinal changes were seen in any group except the 0.8-mg group, which showed chorioretinal vascular attenuation. In 0.1 and 0.2-mg groups, no significant anatomical changes were found except transient hyperreflective dots over the vitreoretinal interface on OCT. In 0.4 and 0.8-mg groups, disruption of the ellipsoid zone and diffuse retinal swelling were observed in the early period on OCT. In the 0.4-mg group, the outer retina was significantly destroyed at day 28, whereas the inner retina was relatively preserved. In the 0.8-mg group, the entire retina was destroyed irreversibly. The b-wave of ERG was reduced immediately in all groups, which recovered fully (0.1- and 0.2-mg groups), partially (0.4-mg group), or never (0.8-mg group). No structural or functional abnormalities were found in the fellow control eyes.. Retinal degeneration following intravitreal injection of SI appears to be dose dependent; retinal damage is reversible at low doses but irreversible at high doses. At a certain dose, the outer retina may be preferably ablated.

Topics: Animals; Disease Models, Animal; Electroretinography; Female; Intravitreal Injections; Iodates; Rabbits; Retina; Retinal Degeneration; Tomography, Optical Coherence; Vitreous Body

Green tea extracts exhibit anti-oxidative and anti-inflammatory actions in different disease conditions. We hypothesized that green tea extract and its catechin constituents ameliorate sodium iodate-induced retinal degeneration in rats by counteracting oxidative stress. In this study, adult Sprague-Dawley rats were intravenously injected with a single dose of sodium iodate. Green tea extract (GTE; Theaphenon-E) or combinations of its catechin constituents, including (-)-epigallocatechin gallate (EGCG), were administered intra-gastrically before injection. Live imaging analysis using confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography showed a progressive increase of degenerating profile across the retinal surface and decrease in thickness of outer nuclear layer (ONL) at Day-14 of post-injection. These lesions were significantly ameliorated by Theaphenon-E and catechin combinations with EGCG. Catechins with exclusion of EGCG did not show obvious protective effect. Histological analyses confirmed that Theaphenon-E and catechins containing EGCG protect the retina by reducing ONL disruption. Retinal protective effects were associated with reduced expression of superoxide dismutase, glutathione peroxidase and caspase-3, and suppression of 8-iso-Prostaglandin F2α generation in the retina. In summary, GTE and its catechin constituents are potent anti-oxidants that offer neuroprotection to the outer retinal degeneration after sodium iodate insult, among which EGCG is the most active constituent.

Topics: Administration, Oral; Animals; Antioxidants; Catechin; Dinoprost; Gene Expression Regulation; Iodates; Ophthalmoscopy; Oxidative Stress; Rats, Sprague-Dawley; Retinal Degeneration; Retinal Pigment Epithelium; Tea

To establish the dose of subretinal sodium iodate (NaIO3) in order to create a toxin-induced large animal model of selective circumscribed atrophy of outer retinal layers, the retinal pigment epithelium (RPE), and photoreceptors, by spectral-domain optical coherence tomography (SD-OCT) and immunocytochemistry.. Fifteen male and female healthy Yorkshire pigs received unilateral subretinal escalating doses of NaIO3 under general anesthesia. In all the animals, volumes of 0.1 to 0.2 mL NaIO3 were injected into the subretinal space of the area centralis through a 23/38-gauge subretinal cannula. Control SD-OCTs were performed 1 and 2 months after the surgery, at which time pigs were euthanized and eyes enucleated. Globes were routinely processed for histologic and immunohistochemical evaluation.. Spectral-domain OCT and immunohistochemistry revealed circumscribed and well-demarcated funduscopic lesions, limited to the outer retinal layers in pigs treated with 0.01 mg/mL subretinal sodium iodate.. The swine model of a controlled area of circumscribed retinal damage, with well-delimited borders, and selectively of the outer layers of the retina presented herein shows several clinical and histologic features of geographic atrophy in AMD. Therefore, it may represent a valuable tool in the investigation of new emerging regenerative therapies that aim to restore visual function, such as stem cell transplantation or optogenetics.

Topics: Animals; Anterior Eye Segment; Biomarkers; Diagnosis, Differential; Disease Models, Animal; Disease Progression; Female; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; Geographic Atrophy; Immunohistochemistry; Iodates; Male; Ophthalmoscopy; Retinal Degeneration; Retinal Pigment Epithelium; Subretinal Fluid; Swine; Tomography, Optical Coherence; Visual Acuity

Studies have shown that mini-αA can protect retinal pigment epithelium (RPE) cells from apoptosis. However, no in vivo study concerning the anti-apoptotic function of mini-αA has been conducted yet.. MTT assay, HE staining and TUNEL assay were used to assess levels of cells, and an animal model was established to examine the protective effects of mini-αA against NaIO3-induced RPE cell apoptosis. Western blot analysis and RT-qPCR were performed to explore the possible mechanism of mini-αA's protective function against NaIO3-induced RPE cell apoptosis.. RESULTS from in vivo and animal experiments showed that mini-αA antagonized NaIO3-induced RPE cell apoptosis. Further investigation into how mini-αA provided protection against NaIO3-induced RPE cell apoptosis showed that mini-αA reduced NaIO3-induced RPE cell apoptosis and autophagy. In addition, unfolded protein response was also involved in the protective effects of mini-αA against NaIO3-induced RPE cell apoptosis.. mini-αA can antagonize RPE cell apoptosis induced by NaIO3. A possible mechanism is by inhibition of apoptosis by repressing autophagy and endoplasmic reticulum stress.

Topics: alpha-Crystallin A Chain; Amino Acid Sequence; Animals; Apoptosis; Cell Line; Humans; Iodates; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Peptides; Protective Agents; Retina; Retinal Degeneration; Retinal Pigment Epithelium

Herein, we have investigated retinal cell-death pathways in response to the retina toxin sodium iodate (NaIO3) both in vivo and in vitro. C57/BL6 mice were treated with a single intravenous injection of NaIO3 (35 mg/kg). Morphological changes in the retina post NaIO3 injection in comparison to untreated controls were assessed using electron microscopy. Cell death was determined by TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining. The activation of caspases and calpain was measured using immunohistochemistry. Additionally, cytotoxicity and apoptosis in retinal pigment epithelial (RPE) cells, primary retinal cells, and the cone photoreceptor (PRC) cell line 661W were assessed in vitro after NaIO3 treatment using the ApoToxGlo™ assay. The 7-AAD/Annexin-V staining was performed and necrostatin (Nec-1) was administered to the NaIO3-treated cells to confirm the results. In vivo, degenerating RPE cells displayed a rounded shape and retracted microvilli, whereas PRCs featured apoptotic nuclei. Caspase and calpain activity was significantly upregulated in retinal sections and protein samples from NaIO3-treated animals. In vitro, NaIO3 induced necrosis in RPE cells and apoptosis in PRCs. Furthermore, Nec-1 significantly decreased NaIO3-induced RPE cell death, but had no rescue effect on treated PRCs. In summary, several different cell-death pathways are activated in retinal cells as a result of NaIO3.

Topics: Animals; Apoptosis; Caspases; Iodates; Mice; Mice, Inbred C57BL; Necrosis; Retinal Degeneration; Retinal Pigment Epithelium

To systematically characterize the effects of NaIO3 on retinal morphology and function.. NaIO3 at 10, 20, or 30 mg/kg was administered by retro-orbital injection into adult C57BL/6J mice. Phenotypic and functional changes of the retina were assessed at 1, 3, 5, and 8 days postinjection by fundus imaging, optical coherence tomography (OCT), ERG, and histology. Direct NaIO3 cytotoxicity on ARPE-19 and 661W cells was quantified using lactate dehydrogenase (LDH) apoptosis assay. Effect of NaIO3 on RPE and photoreceptor gene expression was assessed in vitro and in vivo by quantitative PCR.. While little to no change was observed in the 10 mg/kg NaIO3-injected group, significant retinal anomalies, such as RPE atrophy and retinal thinning, were observed in both 20 and 30 mg/kg NaIO3-injected groups. Gene expression analysis showed rapid downregulation of RPE-specific genes, increase in heme oxygenase 1 expression, and induction of the ratio of Bax to Bcl-2. Electroretinographic response loss and photoreceptor gene repression preceded gross morphological changes. High NaIO3 toxicity on 661W cells was observed in vitro along with reactive oxygen species (ROS) induction. NaIO3 treatment also disrupted oxidative stress, phototransduction, and apoptosis gene expression in 661W cells. Exposure of ARPE-19 cells to NaIO3 increased expression of neurotrophins and protected photoreceptors from direct NaIO3 cytotoxicity.. Systematic characterization of changes associated with NaIO3 injection revealed a large variability in the severity of toxicity induced. Treatment with >20 mg/kg NaIO3 induced visual dysfunction associated with rapid suppression of phototransduction genes and induced oxidative stress in photoreceptors. These results suggest that NaIO3 can directly alter photoreceptor function and survival.

Topics: Animals; Apoptosis; Disease Models, Animal; Iodates; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Pigment Epithelium of Eye; Reactive Oxygen Species; Retinal Degeneration; Tomography, Optical Coherence

Sodium iodate induces RPE atrophy and photoreceptor degeneration, as seen in the pathogenesis of many retinal diseases. We investigated a new approach of analyzing retinal images using confocal scanning laser ophthalmoscopy (cSLO) that allows longitudinal assessment of sodium iodate-induced lesions in the retina of living rats.. A single dose of sodium iodate (25-75 mg/kg) was given intravenously to adult Sprague-Dawley rats. Control animals were given normal saline or sodium iodide. The retina was examined by cSLO and optical coherence tomography (OCT) in living rats, which were then killed for histologic assessments.. Confocal scanning laser ophthalmoscopy revealed the appearance of dark patchy blots in planar images of the retina 7 days after intravenous injection of sodium iodate (25-75 mg/kg). This finding coincided with the observations of degenerative changes in the outer retinal layers in OCT images and in histology of the retina. Further analyses showed a concomitant localization of degenerative profiles in histologic preparations of this retina, suggesting that the blots corresponded to the deteriorating photopigments and outer nuclear layer (ONL). In histologic sections, these degenerative profiles appeared as irregular folds or rosettes in the ONL. Quantitative analyses showed that the changes in blot number were dose dependent, which again coincided with results showing a dose-dependent lesion in the photopigment layer and ONL in histologic sections of the retina.. Sodium iodate-induced degenerative changes can be assessed quantitatively and reliably by in vivo retinal imaging using cSLO in adult rats, allowing efficient evaluation of lesions in a large area of retina in longitudinal studies.

Topics: Animals; Disease Models, Animal; Disease Progression; Iodates; Microscopy, Confocal; Ophthalmoscopy; Rats; Rats, Sprague-Dawley; Retinal Degeneration; Retinal Photoreceptor Cell Outer Segment; Tomography, Optical Coherence

The purpose of this study was to demonstrate the progression of acute retinal injury by correlating histological sections with in vivo spectral-domain optical coherence tomography (SD-OCT) images.. Male C57BL/6 mice were treated intravenously with two different sodium iodate (NaIO3) doses (35 mg/kg or 15 mg/kg). In vivo SD-OCT was performed up to 3 months post-injury. Ex vivo retinal histology, TUNEL and IsolectinB4 immunostaining were also conducted. Quantitative comparison of histopathological images and SD-OCT images was performed.. SD-OCT examination revealed that administration of 35 mg/kg NaIO3 was associated with progressive and irreversible retinal degeneration. On day 3 post-injury, we found numerous apoptotic cells in the outer nuclear layer (ONL) that strongly corresponded to hyper-reflective areas in the SD-OCT images. At 7 d post-injury, SD-OCT images showed irregular-shaped patterns of hyper-reflectivity in the retinal pigment epithelium (RPE) that corresponded with the accumulation of macrophages phagocytosing melanin granules and cell debris. Additionally, we documented hyper-reflective opacities in the vitreous that were most numerous at 7 d. At 3 months post-injury, the neurosensory retina was significantly thinner, predominantly due to progressive photoreceptor (PR) loss. In contrast, administration of 15 mg/kg NaIO3 did not induce hyper-reflectivity of ONL in SD-OCT images, which indicates a lack of massive PR cell death. At 3 months post-injury, SD-OCT images showed the complete restoration of outer retina lamination and restoration of hyper-reflective structural bands. Histological assessment of retinas acquired after the last SD-OCT imaging session revealed complete regeneration of the RPE and considerable improvement of PR architecture.. Our findings showed the high level of effectiveness of SD-OCT imaging for monitoring dynamic changes in retinal morphology following acute retinal injury. Moreover, we demonstrated for the first time that SD-OCT can be used to non-invasively detect regeneration in the damaged retina.

Topics: Animals; Dose-Response Relationship, Drug; Glycoproteins; In Situ Nick-End Labeling; Injections, Intravenous; Iodates; Male; Mice; Mice, Inbred C57BL; Photoreceptor Cells, Vertebrate; Regeneration; Retina; Retinal Degeneration; Retinal Pigment Epithelium; Tomography, Optical Coherence

Age-related macular degeneration (AMD) is a leading cause of blindness in the developed world. The retinal pigment epithelium (RPE) is a critical site of pathology in AMD and αB crystallin expression is increased in RPE and associated drusen in AMD. The purpose of this study was to investigate the role of αB crystallin in sodium iodate (NaIO3)-induced retinal degeneration, a model of AMD in which the primary site of pathology is the RPE. Dose dependent effects of intravenous NaIO3 (20-70 mg/kg) on development of retinal degeneration (fundus photography) and RPE and retinal neuronal loss (histology) were determined in wild type and αB crystallin knockout mice. Absence of αB crystallin augmented retinal degeneration in low dose (20 mg/kg) NaIO3-treated mice and increased retinal cell apoptosis which was mainly localized to the RPE layer. Generation of reactive oxygen species (ROS) was observed with NaIO3 in mouse and human RPE which increased further after αB crystallin knockout or siRNA knockdown, respectively. NaIO3 upregulated AKT phosphorylation and peroxisome proliferator-activator receptor-γ (PPARγ) which was suppressed after αB crystallin siRNA knockdown. Further, PPARγ ligand inhibited NaIO3-induced ROS generation. Our data suggest that αB crystallin plays a critical role in protection of NaIO3-induced oxidative stress and retinal degeneration in part through upregulation of AKT phosphorylation and PPARγ expression.

Topics: alpha-Crystallin B Chain; Animals; Apoptosis; Caspase 3; Cell Death; Disease Models, Animal; Electroretinography; Enzyme Activation; Gene Knockdown Techniques; Humans; Iodates; Macular Degeneration; Mice; Mice, Knockout; Reactive Oxygen Species; Retina; Retinal Degeneration; Retinal Pigment Epithelium; Retinoscopes; RNA Interference; Signal Transduction

The retinal pigment epithelium (RPE) has been reported to demonstrate feasible self-regenerative potential under specific conditions. However, the precise underlying mechanisms involved in this process are still elusive. Here, we performed a sequential morphological, molecular, and functional analysis of retinal injury and subsequent tissue regeneration after intravenous administration of a low dose of sodium iodate (15 mg/kg) in mice over long-term observation, up to 3 months post-injury. To assess the kinetics of the injury/recovery process, the electroretinography (ERG) responses were correlated with ongoing alterations in retinal structure and the global gene expression profile of injured retinas using genome-wide RNA microarray technology, western blotting and immunohistochemical analyses. We observed considerable improvement in the rod cell-mediated ERG response, which was accompanied by the regeneration of RPE within the injury site by the 3rd month post-injury. Our results confirm that the repairing mechanisms within injured retinas involve a significant glial cell reaction marked by glial cell proliferation, migration from their original location toward the injury site, followed by a significant overproduction of NTs such as BDNF, GDNF and NT-3. The global gene expression analysis revealed that initially up-regulated genes associated with cell death, apoptosis, acute response to stress pathways underwent considerable down-regulation in the late post-injury period. Accordingly, the genes implicated in nervous tissue remodeling and neuron development, the regulation of synaptic transmission and the establishment of localization were substantially induced by the 3rd month. Collectively, our observations support the view that Müller glial cells might well play an active role not only in retinal cell reorganization following injury but potentially also in RPE regeneration, which appears to be the key event in retinal reparative process. Furthermore, we provided novel compelling evidence of the crucial role of neurotrophins in the pathophysiology of retinal repair and identified the signaling pathways that are activated during this process.

Topics: Animals; Blotting, Western; Brain-Derived Neurotrophic Factor; Cell Movement; Cell Proliferation; Electroretinography; Fluorescent Antibody Technique, Indirect; Gene Expression Profiling; Gene Expression Regulation; Glial Cell Line-Derived Neurotrophic Factor; Iodates; Mice; Nerve Growth Factors; Neuroglia; Oligonucleotide Array Sequence Analysis; Proliferating Cell Nuclear Antigen; Protein Array Analysis; Regeneration; Retinal Degeneration; Retinal Pigment Epithelium; RNA, Messenger; Signal Transduction

For degenerative retinal diseases, like the acquired form exemplified by age-related macular degeneration (AMD), there is currently no cure. This study was to explore a stem cell therapy and a stem cell based gene therapy for sodium iodate (SI)-induced retinal degeneration in rats. Three cell types, i.e., rat mesenchymal stem cells (rMSCs) alone, erythropoietin (EPO) gene modified rMSCs (EPO-rMSCs) or doxycycline (DOX) inducible EPO expression rMSCs (Tet-on EPO-rMSCs), were transplanted into the subretinal spaces of SI-treated rats. The rMSCs were prepared for transplantation after 3 to 5 passages or modified with EPO gene. During the 8 weeks after the transplantation, the rats treated with rMSCs alone or with two types of EPO-rMSCs were all monitored with fundus examination, fundus fluorescein angiography (FFA) and electroretinogram. The transplantation efficiency of donor cells was examined for their survival, integration and differentiation. Following the transplantation, labeled donor cells were observed in subretinal space and adopted RPE morphology. EPO concentration in vitreous and retina of SI-treated rats which were transplanted with EPO-rMSCs or Tet-on EPO-rMSCs was markedly increased, in parallel with the improvement of retinal morphology and function. These findings suggest that rMSCs transplantation could be a new therapy for degenerative retinal diseases since it can protect and rescue RPE and retinal neurons, while EPO gene modification to rMSCs could be an even better option.

Topics: Animals; Cell Differentiation; Erythropoietin; Gene Transfer Techniques; Iodates; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Rats; Rats, Sprague-Dawley; Retina; Retinal Degeneration

Retinal degenerative diseases targeting the RPE and adjacent photoreceptors affect millions of people worldwide. The field of stem cell- and gene-based therapy holds great potential for the treatment of such diseases. The present study sought to graft genetically engineered mesenchymal stem cells (MSCs) that continuously produce neurotrophin-4 (NT-4) into the murine eye after the onset of acute retinal injury.. C57BL/6 mice were subjected to acute retinal damage using a low dose of sodium iodate (20 mg/kg of body weight), followed by intravitreal injection of lentivirally modified MSC-NT-4 into the right eye. At 3 months after the MSC transplantation grafted cell survival, retinal function and gene expression were analyzed.. Immunofluorescence analysis confirmed that transplanted MSCs survived for at least 3 months after intravitreal injection and preferentially migrated toward sites of injury within the retina. MSC-NT-4 actively produced NT-4 in the injured retina and significantly protected damaged retinal cells, as evaluated by ERG and optical coherence tomography (OCT). Of importance, the long-term therapy with MSC-NT-4 was also associated with induction of prosurvival signaling, considerable overexpression of some subsets of transcripts, including several members of the crystallin β-γ superfamily (Cryba4, Crybb3, Cryba2, Crybb1, Crybb2, Cryba1, and Crygc) and significant upregulation of biological processes associated with visual perception, sensory perception of light stimulus, eye development, sensory organ development, and system development.. Transplantation of genetically modified MSCs that produce neurotrophic growth factors may represent a useful strategy for treatment of different forms of retinopathies in the future.

Topics: Animals; Biomarkers; Blotting, Western; Cell Movement; Cell Survival; Disease Models, Animal; Electroretinography; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Fluorescent Antibody Technique, Indirect; Follow-Up Studies; Gene Expression Regulation; Gene Transfer Techniques; Genetic Engineering; Genetic Therapy; Genetic Vectors; Intravitreal Injections; Iodates; Lentivirus; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Nerve Growth Factors; Neuroprotective Agents; Real-Time Polymerase Chain Reaction; Retina; Retinal Degeneration

Sodium iodate (NaIO(3))-induced retina injury is one of models that is commonly used to study various retinal diseases caused by retinal pigment epithelium (RPE) injury such as AMD. Previous researches have revealed that RPE and photoreceptors are main impaired objects in this model. By comparison, intra-retinal layer has not been studied in detail after NaIO(3) administration. In this study, we present evidences that intra-retinal neurons can be directly injured by NaIO(3) at early stage and that the morphology had taken obvious changes, the decreased areas of dendritic fields of dopaminergic amacrine cells (DA-ACs), horizontal cells, and melanopsin-expressing retinal ganglion cells (mRGCs). Moreover, we found that miRNA 133b that was considered specifically to express in midbrain dopaminergic neurons was markedly upregulated in retinal DA-ACs after NaIO(3) administration. The overexpression of mir-133b negatively regulated the expression of pitx3, an important transcription factor, and led to a series of deficits of DA-ACs such as TH and D2 receptor expression and DA producing, which may play a causative role in pathological events of horizontal cells and mRGCs. After mir-133b was interfered with mir-133b/RNAi, not only those deficits were rescued, but also the amplitude of b-wave and summed OPs of ERG were improved significantly. In conclusion, our data demonstrate, for the first time, that intra-retinal neurons can be directly injured by NaIO(3) at early stage, and that mir-133b level effectively controls synaptic contacts or neural interactions among DA-ACs, horizontal cells, and mRGCs. Delivering mir-133b/RNAi intravitreally can rescue NaIO(3)-induced failure and improve visual function by restoring synaptic contacts.

Topics: Amacrine Cells; Animals; Dopamine; Electroretinography; Glutamate Decarboxylase; Iodates; Mesencephalon; MicroRNAs; Rats; Retinal Degeneration; Retinal Ganglion Cells; RNA Interference; Rod Opsins; Signal Transduction

An ultrahigh resolution spectral domain optical coherence tomography (SD-OCT) system is used to observe for the first time in vivo the early effect of sodium iodate (NaIO3) toxicity on retinal morphology. Retinal degeneration is induced in rats via tail vein injection of NaIO3 and structural changes in the outer retina are assessed longitudinally at baseline and 1, 2, 3, 6, 8, and 10 h, and 12 post drug administration with OCT, H&E histology, and IgG immunochemistry. Disruption of the structural integrity and changes in the optical reflectivity of the photoreceptor inner (IS) and outer segment (OS) layers are observed as early as 1 h post NaIO3 injection. A new layer is observed in the OCT tomograms to form between the retinal pigmented epithelium and the photoreceptors OS a few hours post NaIO3 injection. The dynamics and the low optical reflectivity of this layer, as well as cell swelling and disruption of the blood-retina barrier observed in the histological and immunohistochemistry cross-sections suggest that the layer corresponds to temporary fluid accumulation in the retina. Results from this study demonstrate the effectiveness of OCT technology for monitoring dynamic changes in the retinal morphology and provide better understanding of the early stages of outer retina degeneration induced by NaIO3 toxicity.

Topics: Animals; Disease Models, Animal; Female; Imaging, Three-Dimensional; Iodates; Optical Phenomena; Rats; Rats, Long-Evans; Retinal Degeneration; Retinal Photoreceptor Cell Outer Segment; Retinal Pigment Epithelium; Time Factors; Tomography, Optical Coherence

Our purpose was to find a method to create a large animal model of inducible photoreceptor damage. To this end, we tested in domestic swine the efficacy of two chemical toxins, known to create photoreceptor damage in other species: Iodoacetic Acid (IAA) and Sodium Iodate (NaIO(3)). Intravenous (IV) administration of NaIO(3) up to 90 mg/kg had no effect on retinal function and 110 mg/kg was lethal. IV administration of IAA (5-20 mg/kg) produced concentration-dependent changes in visual function as measured by full-field and multi-focal electroretinograms (ffERG and mfERG), and 30 mg/kg IAA was lethal. The IAA-induced effects measured at two weeks were stable through eight weeks post-injection, the last time point investigated. IAA at 7.5, 10, and 12 mg/kg produce a concentration-dependent reduction in both ffERG b-wave and mfERG N1-P1 amplitudes compared to baseline at all post-injection times. Comparisons of dark- and light-adapted ffERG b-wave amplitudes show a more significant loss of rod relative to cone function. The fundus of swine treated with ≥10 mg/kg IAA was abnormal with thinner retinal vessels and pale optic discs, and we found no evidence of bone spicule formation. Histological evaluations show concentration-dependent outer retinal damage that correlates with functional changes. We conclude that NaIO(3,) is not an effective toxin in swine. In contrast, IAA can be used to create a rapidly inducible, selective, stable and concentration-dependent model of photoreceptor damage in swine retina. Because of these attributes this large animal model of controlled photoreceptor damage should be useful in the investigation of treatments to replace damaged photoreceptors.

Topics: Animals; Blood Glucose; Dark Adaptation; Disease Models, Animal; Dose-Response Relationship, Drug; Electroretinography; Enzyme Inhibitors; Infusions, Intravenous; Iodates; Iodoacetic Acid; Photic Stimulation; Photoreceptor Cells, Vertebrate; Retinal Degeneration; Sus scrofa

Stem cell regeneration of damaged tissue has recently been reported in many different organs. Here, we investigated the mobilization of different stem/progenitor cell (SPC) populations into the peripheral blood (PB), their subsequent homing to the injured retina (IR) and contribution to its regeneration in a retinal pigment epithelium (RPE) damage model induced by sodium iodate (NaIO(3)).. Mobilization of SPCs was evaluated by flow cytometry. SPCs distribution in IR was assessed using bone marrow (BM)-derived GFP(+)Lin(-) cells transplanted intravenously into NaIO(3)-treated C57Bl/6 mice. The quantity of the chemokine SDF-1 in PB and IR was measured by ELISA and qRT-PCR, respectively. Apoptosis (TUNEL assay), cell proliferation (PCNA analysis) as well as functional retinal activity (electroretinogram) were examined at several time points after NaIO(3) administration.. Mobilization of SPCs along with the highest cell proliferation and massive apoptosis within IR were observed on the third day after NaIO(3) administration. Similarly, donor GFP(+)Lin(-) cells were detected in the retina as soon as day 4 after NaIO(3) injection. Plasma levels of SDF-1 did not differ significantly in mice exposed to NaIO(3) compared to healthy controls, however mRNA for SDF-1 was overexpressed locally in IR. Functional retinal recovery was not achieved.. Our study provides evidence that BM SPCs egress into PB and home to the injured retina, but are not capable of restoring its function. These results indicate that if the range of retinal destruction is profound, endogenous regeneration is ineffective and may ultimately require adjuvant therapeutic transplantation of specific SPCs subpopulations.

Topics: Animals; Antigens, Ly; Apoptosis; Blood Circulation; Bone Marrow Cells; Cell Proliferation; Chemokine CXCL12; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; In Situ Nick-End Labeling; Iodates; Leukocyte Common Antigens; Membrane Proteins; Mice; Mice, Inbred C57BL; Regeneration; Retinal Degeneration; Retinal Pigment Epithelium; Reverse Transcriptase Polymerase Chain Reaction

Sequential morphological and functional features of retinal damage in mice exposed to different doses (40 vs. 20 mg/kg) of sodium iodate (NaIO(3)) were analyzed. Retinal morphology, apoptosis (TUNEL assay), and function (electroretinography; ERG) were examined at several time points after NaIO(3) administration. The higher dose of NaIO(3) caused progressive degeneration of the whole retinal area and total suppression of scotopic and photopic ERG. In contrast, the lower dose induced much less severe degeneration in peripheral part of retina along with a moderate decline of b- and a-wave amplitudes in ERG, corroborating the presence of regions within retina that retain their function. The peak of photoreceptor apoptosis was found on the 3rd day, but the lower dose induced more intense reaction within the central retina than in its peripheral region. In conclusion, these results indicate that peripheral area of the retina reveals better resistance to NaIO(3) injury than its central part.

Topics: Animals; Apoptosis; Electroretinography; Iodates; Male; Mice; Mice, Inbred C57BL; Photoreceptor Cells; Pigment Epithelium of Eye; Retina; Retinal Degeneration; Specific Pathogen-Free Organisms

To investigate the protective effects of non-mitogenic human acidic fibroblast growth factor on retinal degeneration induced by NaIO(3) in rats.. Retinal degeneration was induced in adult male Wistar rats via caudal-vein injection of 1% NaIO(3) at 50 mg/kg. One h after NaIO(3) treatment, the right eyes received intravitreal injection of 2.5 microg nm-haFGF in 10 microL saline and the left eyes received saline alone as vehicle-treated eyes. Retinal function in rats was evaluated by electroretinogram (ERG) before injection and 1, 7, and 21 days postinjection. Additional rat eyes were enucleated 7 and 21 days postinjection, fixed, and processed for histological examination.. A model of retinal degeneration in rat was established successfully using NaIO(3) injection. Significant decreases in both ERG a- and b-wave amplitudes were detected in NaIO(3)-injected rats when compared with the normal animals (P < 0.05) on day 7 postinjection. Importantly, at the seventh day after intravitreal nm-haFGF treatment on NaIO(3)-injected rats, the nm-haFGF-treated eyes showed a significant improvement in the ERG amplitudes of both a- and b-waves when compared with vehicle-treated eyes (P < 0.05). In addition, the disruptions of photoreceptor outer segments and the retinal pigment epithelium monolayer were much less frequently observed in the nm-haFGF-treated eyes than the vehicle-treated eyes, and the outer nuclear layer thickness in the nm-haFGF-treated eyes was similar to that of the normal eyes.. Intravitreal delivery of nm-haFGF appears to have neuroprotective effect on retinal degeneration induced by NaIO(3).

Topics: Animals; Disease Models, Animal; Electroretinography; Fibroblast Growth Factor 1; Humans; Iodates; Male; Pigment Epithelium of Eye; Rats; Rats, Wistar; Retinal Degeneration; Retinal Photoreceptor Cell Outer Segment

The differentiation of rat bone marrow mesenchymal stem cells (MSCs) was investigated in a retinal pigment epithelium (RPE) damage model induced by the administration of sodium iodate.. Cultured rat MSCs were transfected with enhanced green fluorescent protein and transplanted into the subretinal space of rats injected 4 days earlier with sodium iodate. Immunofluorescence analysis was performed 5 weeks later.. The transduction efficiency was 99.9%. Viable MSCs were detected 5 weeks after transplantation, mainly in the subretinal space. The cells expressed pan-cytokeratin, glial fibrillary acidic protein and rhodopsin.. Bone marrow MSCs transplanted into the subretinal space of sodium iodate-injected rats have the ability to differentiate into RPE, photoreceptor and glial lineage cells.

Topics: Animals; Bone Marrow Cells; Cell Differentiation; Disease Models, Animal; Green Fluorescent Proteins; Injections; Iodates; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Rats; Rats, Wistar; Retinal Degeneration; Retinal Pigment Epithelium; Transfection

We characterized changes in the visual behavior of mice in which a loss of the retinal pigment epithelium (RPE) was experimentally induced with intravenous (i.v.) administration of sodium iodate (NaIO3). We compared and correlated these changes with alterations in neural retinal structure and function. RPE loss was induced in 4-6 week old male C57BL/6 mice with an i.v. injection of 1% NaIO3 at three concentrations: 35, 50, or 70 mg/kg. At 1, 3, 7, 14, 21, and 28 days (d) as well as 6 months post injection (PI) a behavioral test was performed in previously trained mice to evaluate visual function. Eye morphology was then assessed for changes in both the RPE and neural retina. NaIO3-induced RPE degeneration was both dose and PI time dependent. Our low dose showed no effects, while our high dose caused the most damage, as did longer PI times at our intermediate dose. Using the intermediate dose, no changes were detectable in either visual behavior or retinal morphology at 1 d PI. However, at 3 d PI visual behavior became abnormal and patchy RPE cell loss was observed. From 7 d PI onward, changes in retinal morphology and visual behavior became more severe. At 6 months PI, no recovery was seen in any of these measures in mice administered the intermediate dose. These results show that NaIO3 dosage and/or time PI can be varied to produce different, yet permanent deficits in retinal morphology and visual function. Thus, this approach should provide a unique system in which the onset and severity of RPE damage, and its consequences can be manipulated. As such, it should be useful in the assessment of rescue or mitigating effects of retinal or stem cell transplantation on visual function.

Topics: Animals; Dose-Response Relationship, Drug; Injections, Intravenous; Iodates; Male; Mice; Mice, Inbred C57BL; Models, Animal; Pigment Epithelium of Eye; Retina; Retinal Degeneration; Time Factors; Vision, Ocular

To investigate the possible protective effect of hepatocyte growth factor (HGF) against degeneration of photoreceptors and retinal pigment epithelium (RPE) in vivo.. Sprague-Dawley (SD) rats received an intravitreal injection of HGF in the right eye. The left eye was injected with vehicle as a control. Two days after the intravitreal injections, rats were administered 40 mg/kg of sodium iodate (NaIO3) intravenously. Scotopic ERGs were elicited by different stimulus intensities with a maximum luminance of 0.84 log cds/m2. To evaluate RPE function, the azide response was evoked by intravenous injection of 0.1 mg sodium azide. These electrophysiological measurements were conducted on days 4, 7, 14, and 28 after the NaIO3 injections. After recording ERGs or azide response, animals were sacrificed for quantification of the histological change and immunohistochemical analysis using antibodies against RPE 65.. The threshold for the scotopic b-wave was significantly lower in HGF-treated eyes than in untreated control eyes (p < 0.005), and maximum b-wave amplitudes (Vbmax) were significantly larger in HGF-treated eyes (p < 0.05) across all experimental time points after NaIO3 injection. Azide response amplitudes were significantly larger in the HGF-treated eyes than in the untreated eyes (p < 0.05). The structure of the outer retina was preserved to a greater degree in the HGF-treated eyes than in the untreated eyes (p < 0.05). Immunohistochemical analysis demonstrated that irregular alignment of the outer nuclear layer was confined to the retinal area that was not stained with RPE 65.. Our results indicated that an intravitreal injection of HGF provided significant protection against degeneration of the photoreceptor and RPE induced by systemic administration of NaIO3. This suggests that HGF could be used as a therapeutic agent for degeneration of photoreceptors as well as RPE.

Topics: Animals; Carrier Proteins; cis-trans-Isomerases; Electroretinography; Eye Proteins; Hepatocyte Growth Factor; Injections; Iodates; Male; Photoreceptor Cells, Vertebrate; Pigment Epithelium of Eye; Rats; Rats, Sprague-Dawley; Retinal Degeneration; Sodium Azide; Vitreous Body

Stem cell regeneration of damaged tissue has recently been reported in many different organs. Since the loss of retinal pigment epithelium (RPE) in the eye is associated with a major cause of visual loss - specifically, age-related macular degeneration - we investigated whether hematopoietic stem cells (HSC) given systemically can home to the damaged subretinal space and express markers of RPE lineage. Green fluorescent protein (GFP) cells of bone marrow origin were used in a sodium iodate (NaIO(3)) model of RPE damage in the mouse. The optimal time for adoptive transfer of bone marrow-derived stem cells relative to the time of injury and the optimal cell type [whole bone marrow, mobilized peripheral blood, HSC, facilitating cells (FC)] were determined by counting the number of GFP(+) cells in whole eye flat mounts. Immunocytochemistry was performed to identify the bone marrow origin of the cells in the RPE using antibodies for CD45, Sca-1, and c-kit, as well as the expression of the RPE-specific marker, RPE-65. The time at which bone marrow-derived cells were adoptively transferred relative to the time of NaIO(3) injection did not significantly influence the number of cells that homed to the subretinal space. At both one and two weeks after intravenous (i.v.) injection, GFP(+) cells of bone marrow origin were observed in the damaged subretinal space, at sites of RPE loss, but not in the normal subretinal space. The combined transplantation of HSC+FC cells appeared to favor the survival of the homed stem cells at two weeks, and RPE-65 was expressed by adoptively transferred HSC by four weeks. We have shown that systemically injected HSC homed to the subretinal space in the presence of RPE damage and that FC promoted survival of these cells. Furthermore, the RPE-specific marker RPE-65 was expressed on adoptively transferred HSC in the denuded areas.

Topics: Animals; Apoptosis; Cell Lineage; Cells, Cultured; Disease Models, Animal; Green Fluorescent Proteins; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Immunohistochemistry; Iodates; Luminescent Agents; Male; Mice; Mice, Inbred C57BL; Pigment Epithelium of Eye; Pluripotent Stem Cells; Retinal Degeneration

To investigate the in vivo effects of tissue factor pathway inhibitor 2 (TFPI-2), which stimulates proliferation of retinal pigment epithelial cells, but not the proliferation of fibroblast and vascular endothelial cells in vitro, on retinal degeneration using a sodium-iodate (SI)-induced model in rabbits and Royal Collage of Surgeons (RCS) rats.. 79 microg of recombinant TFPI-2 (rTFPI-2) or vehicle alone was injected intravitreously to 18 eyes of 12 pigmented rabbits a day after 20 mg/kg of SI was intravenously administered. Retinal function was assessed 4, 7, 14, and 21 days after the injection by analysing amplitudes of the c-wave of a bright flash electroretinogram. Additionally, 10 microg of rTFPI-2 or vehicle alone was injected intravitreously to 11 eyes of RCS rats at both 3 and 4 weeks old, then the retina was examined histologically at 5 weeks old.. The rTFPI-2-treated eyes in rabbits showed a significantly less decrease in the relative amplitude of the c-wave than control eyes on days 4 and 7. The thickness of the outer nuclear layer was significantly thicker and the vacuole in the photoreceptor layer was less frequently observed in the rTFPI-2-treated RCS rats than the controls.. Intravitreal injection of TFPI-2 rescues SI-induced retinal degeneration in rabbits and naturally occurring retinal degeneration in RCS rats at least partly. These results may suggest that this compound can be utilized in the treatment of retinal degeneration.

Topics: Animals; Disease Models, Animal; Electroretinography; Glycoproteins; Injections; Iodates; Male; Pigment Epithelium of Eye; Rabbits; Recombinant Proteins; Retinal Degeneration; Vitreous Body

Retinal degeneration induced by sodium iodate (NaIO( 3)) in mice was evaluated morphologically.. Male and female ICR and C57BL mice were intraperitoneally administered 100 mg/kg NaIO(3) at 7 weeks of age, and were killed 6, 12, 24 hrs, and 3, 7 and 28 days after the treatment. Retinas were examined histologically, ultrastructurally, immunohistochemically, and by the TUNEL method.. Retinal degeneration was evoked in all NaIO(3)-treated mice. The primary site of damage appeared in the retinal pigment epithelial (RPE) cells followed by photoreceptor cell degeneration. Initially, the RPE cells showed necrosis starting 6 hrs post-NaIO(3), followed by photoreceptor outer segment disruption and photoreceptor cell apoptosis at 24 hrs; photoreceptor cell apoptosis peaked at day 3 and was completed by day 7. At day 3, Müller cell proliferation, macrophage migration within the retina, and regeneration of damaged RPE cells occurred. Finally at day 7 and day 28, the retina showed a mosaic pattern of relatively normal retina and areas lacking RPE cells and photoreceptor cells.. RPE cell necrosis followed by photoreceptor cell apoptosis and the resulting mosaic pattern of the retina phenotypically resembles gyrate atrophy of the choroid and retina.

Topics: Animals; Apoptosis; Female; Glial Fibrillary Acidic Protein; Iodates; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Microscopy, Electron; Photoreceptor Cells; Pigment Epithelium of Eye; Proliferating Cell Nuclear Antigen; Retinal Degeneration

Outer retinal degenerations can cause severe visual handicap. Specific treatment is lacking. There is good histologic evidence that even in the face of total photoreceptor loss the ganglion cells remain viable. This study evaluates the possibility of eliciting an evoked potential by electrical stimulation of rabbit eyes with experimentally induced outer retinal degenerations. Electrical stimulation using a bipolar contact-lens electrode was performed in normal rabbits as well as in rabbits with experimentally induced outer retinal degenerations. Outer retinal degenerations were induced by injecting intravenously either monoiodoacetic acid (IAA) or sodium iodate (NaIO3). After administration of IAA or NaIO3, the electroretinogram was absent or markedly reduced and, histologically, the photoreceptor layer was severely damaged. However, the electrically evoked visual cortical response could nonetheless be elicited. We conclude that electrical stimulation of the globe can elicit evoked potentials from the visual cortex despite severe outer retinal damage. These results provide support for future efforts toward testing the feasibility of bypassing damaged outer retina and electrically stimulating the inner retina of patients with profound visual loss from retinitis pigmentosa.

Topics: Animals; Electric Stimulation; Electroretinography; Evoked Potentials, Visual; Iodates; Iodoacetates; Iodoacetic Acid; Rabbits; Retina; Retinal Degeneration; Visual Cortex

Acute experimental retinal degeneration was induced in 3-month-old mice with sodium iodate (NaIO3) injection to investigate the effect of bright light with electroretinography (ERG). Eight C 57 black male mice were anesthetized. The ERG was recorded before and 24 h after the injection of NaIO3. Next, only one eye of each mouse was exposed to a bright light of 3.0 x 10(4) lx white light for 30 min. Ten hours later, ERGs of both the light-exposed and the unexposed eye were recorded. The amplitudes and peak latencies of the a wave and b wave were measured. The ERG was recorded as both eyes were exposed to stimulating flashes that were given in an increasing order of 0.6 log unit steps from the dimmest flash to produce a detectable ERG. The ERG from the light-exposed eye showed a distinctly elevated threshold (approx 2.0 log), while the contralateral unexposed eye did not. The peak latencies of both waves were significantly prolonged by exposure to light. In conclusion, light exposure affected ERG thresholds in mice with experimentally induced acute retinal degeneration.

Topics: Animals; Electroretinography; Injections; Iodates; Light; Male; Mice; Mice, Inbred C57BL; Radiation Injuries, Experimental; Retina; Retinal Degeneration; Sensory Thresholds

Retinitis pigmentosa with attendant photoreceptor loss can cause a profound visual handicap. We have postulated that an intraocular prosthesis that could electrically stimulate the inner retina might provide vision to some of these patients. For such a prosthesis to be feasible, electrical stimulation of the inner retina must elicit a focal retinal response. The stimulating current densities required to elicit such a response must not result in irreversible toxic reactions at the electrode-tissue interface.. To test the feasibility of this approach, we used bipolar platinum wire electrodes to electrically stimulate the inner retinal surface in bullfrog eyecup preparations and, using similar methods, we electrically stimulated rabbit eyes after injecting intravenous sodium iodate (40 mg/kg), a retinal pigment epithelial toxin with secondary effects on the photoreceptors.. Surface electrical stimulation of the inner retina in normal eyes and in eyes with outer retinal degeneration can elicit a localized retinal response. The threshold stimulating currents resulted in charge densities of 2.98 microcoulombs per square centimeter (bullfrog), 8.92 microC/cm2 (normal rabbit), and 11.9 microC/cm2 (rabbit retinas with outer retinal degenerations). These charge densities are within the previously delineated safe limits for long-term electrical stimulation of neural tissue using platinum microelectrodes (100 microC/cm2).. Multifocal electrical stimulation of the retina might be a viable approach to provide some vision to patients who have profound visual loss due to outer retinal degenerations.

Topics: Animals; Electric Stimulation; Electrophysiology; Interneurons; Iodates; Microelectrodes; Organ Culture Techniques; Rabbits; Rana catesbeiana; Retina; Retinal Degeneration; Retinal Ganglion Cells; Sensory Thresholds

Intravenous sodium iodate damages the retinal pigment epithelium, causing immediate loss of the electroretinogram c-wave and eventual pigmentary retinopathy. L-cystein, an agent that enhances the c-wave, has been reported to prevent the late development of pigmentary degeneration. We found in rabbits that L-cystein given 30 min before, or simultaneously with (but not 30 min after) sodium iodate also blocks the loss of the c-wave. This result occurred at doses of L-cystein lower than those needed to produce enhancement of the c-wave, suggesting that these two actions of L-cystein may be independent. The iodate-blocking action of L-cystein may depend on chemical interaction.

Topics: Animals; Cysteine; Electroretinography; Iodates; Pigment Epithelium of Eye; Rabbits; Retinal Degeneration

Topics: Animals; Docosahexaenoic Acids; Fatty Acids, Unsaturated; Iodates; Iodine; Rabbits; Retinal Degeneration; Sulfates; Zinc; Zinc Sulfate

The authors have obtained evidence that destruction of the retinal pigment epithelium (RPE) causes choriocapillaris (CC) atrophy. The observations led us to hypothesize that the RPE modulates CC structure and function. Rabbits received injections of sodium iodate, which selectively destroyed the RPE. The authors killed the rabbits at various times after iodate and examined the RPE and CC by fluorescein angiography, fundus photography, and light and electron microscopy. Fluorescein angiography and fundus photography revealed a pattern of retinopathy similar to that described by other investigators, eg, blood-retinal barrier breakdown and the patchy nature of the RPE/CC degeneration. One week after injection of iodate, the RPE transformed into a mixture of flattened, depigmented cells and plump, highly pigmented ones lying along Bruch's membrane. The CC appeared normal by light microscopy, but electron microscopy revealed changes indicating CC atrophy: degenerating endothelial cells (EC), EC that appeared normal but had reduced numbers of fenestrae, and pericapillary basal laminae that looped away from the endothelium, as if the latter had shrunk. One month after iodate, patches of Bruch's membrane were devoid of RPE, which was replaced by scar tissue. The CC was markedly atrophic over these patches, having reduced numbers of profiles and smaller lumina in those which remained. The CC appeared normal over areas where RPE remained. Eleven weeks after iodate, the light microscopic picture parallelled that seen 1 month after injection, but the patchy RPE degeneration was more extensive. By electron microscopy, the CC profiles over areas devoid of RPE showed severe atrophy. Degenerating EC were more numerous. EC adjacent to areas of RPE loss had few or no fenestrae. Here, capillaries were encased in dense, collagenous, connective tissue, unlike the CC of normal rabbits. These changes were not seen where the RPE still covered Bruch's membrane. These observations suggest that RPE modulates CC structure and function. The authors propose that a diffusible vascular modulating factor produced by RPE cells does this.

Topics: Animals; Atrophy; Capillaries; Choroid; Endothelium; Fibroblasts; Fluorescein Angiography; Iodates; Lysosomes; Pigment Epithelium of Eye; Rabbits; Retina; Retinal Degeneration; Time Factors

Absence of the choriocapillaris (CC) was observed histopathologically in human eyes with retinitis pigmentosa (RP). It was noted in areas where the overlying retinal pigment epithelium (RPE) was absent. Analysis of our material, as well as a review of the literature dealing with RP and related entities, as well as a number of other fundus disorders, suggested that the disappearance of the CC is secondary to REP degeneration. An experimental model using intravenous sodium iodate produced a similar sequence of events in the rabbit. We suggest that the RPE modulates structure and function of the CC. There is possibly a diffusable biochemical vascular modulation factor (VMF) which is required for normal CC fenestrae formation and maintenance, which is liberated by the normal RPE, and acts upon the vascular endothelium. Lack of VME causes the endothelium to lose its fenestrae and the vessel to occlude. This RPE-CC interaction is a further facet of the RPE which requires exploration in depth.

Topics: Aged; Animals; Capillaries; Choroid; Disease Models, Animal; Female; Humans; Iodates; Pigment Epithelium of Eye; Rabbits; Retinal Degeneration; Retinitis Pigmentosa