Studies on the Role of Afferent Activity in the Visual Pathways of the Cat. I. Mechanisms Involved in the Control of Geniculate Cell Size. II. Control of the Critical Period After Dark-Rearing

Two studies were conducted examining the role of afferent activity on synaptic connectivity in the cat's visual pathways. The first study investigated the effects of retinal inactivity on cell size in the lateral geniculate nucleus (LGN). A complete retinal blockade was produced in one eye of 7-week-old kittens by intravitreal injections of tetrodotoxin (TTX). Within one week, cell shrinkage of ~20% in laminae with input from the inactive eye was observed in the binocular and monocular segments of the LGN. Cell growth of 10% was observed in active laminae only in the binocular segment. Adult cats subjected to one week of monocular TTX treatment and kittens placed in the dark during the treatment period underwent uniform changes in cell size of ~20% throughout the binocular and monocular segments of the LGN. The cell size changes in the monocular segment of the kittens left in the light, and throughout the LGN of the kittens placed in the dark and of the adult cats were not indicative of a competitive response to differential activity from the two eyes. The results suggest a strong control of LGN cell size by afferent (retinal) activity. In the second study, cats were reared in the dark from birth until adulthood, then subjected to various visual exposure paradigms to test their residual cortical plasticity. Animals allowed two weeks of binocular visual exposure after dark-rearing, then monocularly lid-sutured underwent changes in cortical ocular dominance in response to the monocular deprivation. Animals which were monocularly deprived immediately upon removal from the dark and 25 days later reverse-sutured for 4-6 months (closure of initially open eye, opening of previously sutured eye) underwent shifts in ocular dominance towards the experienced eye both after the initial monocular deprivation and again in response to reverse-suturing. The LGN of dark-reared/monocularly deprived animals did not exhibit any morphological abnormalities. Depletion of cortical norepinephrine reduced but did not abolish the sensitivity of the dark-reared cortex to monocular deprivation. Visual exposure for four weeks after birth, followed by extended dark-rearing did not halt the subsequent prolongation of cortical plasticity in the dark.</p

Use of Intravitreal Triamcinolone in the Treatment of Macular Edema Related to Retinal Vein Occlusion

ObjectiveTo analyze the increasing trend of intravitreal triamcinolone (IVTA) use in the treatment of retinal vein occlusion-related macular edema.MethodsWe performed MEDLINE/PUBMED searches (September 1984 - December 2007) to identify articles containing the keywords macular edema and triamcinolone. Case reports, reviews and abstracts were identified from references in the reviewed literature. This review focuses on literature published during the past 7 years with more than two-thirds of the articles that we reviewed being printed during the past 5 years. These reports analyzed the success of IVTA in the treatment of macular edema over a 12 month course of time.ResultsThe majority of studies suggested promising results for short time periods (4-6 months) after IVTA treatments. However, long term results were not encouraging.ConclusionsThe success of IVTA therapy for short durations has been the impetus for development of sustained release devices to be used in the treatment of macular edema associated with various retinal diseases including edema related to retinal vein occlusion

Clinical applications of the sustained-release dexamethasone implant for treatment of macular edema

Macular edema is one of the leading causes of vision loss among patients with retinal vein occlusion, diabetic retinopathy, and posterior chamber inflammatory disease. However, the treatment of macular edema is considerably limited by the difficulty in delivering effective doses of therapeutic agents into the vitreous cavity. In recent years, the development of a sustained-release dexamethasone intravitreal implant (Ozurdex®) has enabled more controlled drug release at a stable rate over a long period of time, with a potentially lower rate of adverse events. Clinical studies indicate that this dexamethasone implant is a promising new treatment option for patients with persistent macular edema resulting from retinal vein occlusion, diabetic retinopathy, and uveitis or Irvine-Gass syndrome

Humanin G (HNG) protects age-related macular degeneration (AMD) transmitochondrial ARPE-19 cybrids from mitochondrial and cellular damage.

Age-related macular degeneration (AMD) ranks third among the leading causes of visual impairment with a blindness prevalence rate of 8.7%. Despite several treatment regimens, such as anti-angiogenic drugs, laser therapy, and vitamin supplementation, being available for wet AMD, to date there are no FDA-approved therapies for dry AMD. Substantial evidence implicates mitochondrial damage and retinal pigment epithelium (RPE) cell death in the pathogenesis of AMD. However, the effects of AMD mitochondria and Humanin G (HNG), a more potent variant of the mitochondrial-derived peptide (MDP) Humanin, on retinal cell survival have not been elucidated. In this study, we characterized mitochondrial and cellular damage in transmitochondrial cybrid cell lines that contain identical nuclei but possess mitochondria from either AMD or age-matched normal (Older-normal (NL)) subjects. AMD cybrids showed (1) reduced levels of cell viability, lower mtDNA copy numbers, and downregulation of mitochondrial replication/transcription genes and antioxidant enzyme genes; and (2) elevated levels of genes related to apoptosis, autophagy and ER-stress along with increased mtDNA fragmentation and higher susceptibility to amyloid-β-induced toxicity compared to NL cybrids. In AMD cybrids, HNG protected the AMD mitochondria, reduced pro-apoptosis gene and protein levels, upregulated gp130 (a component of the HN receptor complex), and increased the protection against amyloid-β-induced damage. In summary, in cybrids, damaged AMD mitochondria mediate cell death that can be reversed by HNG treatment. Our results also provide evidence of Humanin playing a pivotal role in protecting cells with AMD mitochondria. In the future, it may be possible that AMD patient's blood samples containing damaged mitochondria may be useful as biomarkers for this condition. In conclusion, HNG may be a potential therapeutic target for treatment of dry AMD, a debilitating eye disease that currently has no available treatment. Further studies are needed to establish HNG as a viable mitochondria-targeting therapy for dry AMD

Terms non-exudative and non-neovascular: awaiting entry at the doors of AMD reclassification

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Dexamethasone Intravitreal Implant as Adjunctive Therapy to Ranibizumab in Neovascular Age-Related Macular Degeneration: A Multicenter Randomized Controlled Trial

Purpose: To evaluate the efficacy and safety of dexamethasone intravitreal implant 0.7 mg (DEX) as adjunctive therapy to ranibizumab in neovascular age-related macular degeneration (nvAMD). Procedures: This was a 6-month, single-masked, multicenter study. Patients were randomized to DEX implant (n = 123) or sham procedure (n = 120) and received 2 protocol-mandated intravitreal ranibizumab injections. The main outcome measure was injection-free interval to first as-needed ranibizumab injection. Results: DEX increased the injection-free interval versus sham (50th percentile, 34 vs. 29 days; 75th percentile, 85 vs. 56 days; p = 0.016). 8.3% of DEX versus 2.5% of sham-treated patients did not require rescue ranibizumab (p = 0.048). Visual acuity and retinal thickness outcomes were similar in DEX and sham-treated patients. Only reports of conjunctival hemorrhage (18.2 vs. 8.5%) and intraocular pressure elevation (13.2 vs. 4.2%) were significantly different in the DEX versus the sham treatment groups. Conclusion: DEX reduced the need for adjunctive ranibizumab treatment and showed acceptable tolerability in nvAMD patients

Memantine, Simvastatin, and Epicatechin Inhibit 7-Ketocholesterol-induced Apoptosis in Retinal Pigment Epithelial Cells But Not Neurosensory Retinal Cells In Vitro

Purpose: 7-ketocholesterol (7kCh), a natural byproduct of oxidation in lipoprotein deposits, is implicated in the pathogenesis of diabetic retinopathy and age-related macular degeneration (AMD). This study was performed to investigate whether several clinical drugs can inhibit 7kCh-induced caspase activation and mitigate its apoptotic effects on retinal cells in vitro. Method: Two populations of retinal cells, human retinal pigment epithelial cells (ARPE-19) and rat neuroretinal cells (R28), were exposed to 7kCh in the presence of the following inhibitors: Z-VAD-FMK (pan-caspase inhibitor), simvastatin, memantine, epicatechin, and Z-IETD-FMK (caspase-8 inhibitor) or Z-ATAD-FMK (caspase-12 inhibitor). Caspase-3/7, -8, and -12 activity levels were measured by fluorochrome caspase assays to quantify cell death. IncuCyte live-cell microscopic images were obtained to quantify cell counts. Results: Exposure to 7kCh for 24 hours significantly increased caspase activities for both ARPE-19 and R28 cells (P &lt; 0.05). In ARPE cells, pretreatment with various drugs had significantly lower caspase-3/7, -8, and -12 activities, reported in % change in mean signal intensity (msi): Z-VAD-FMK (48% decrease, P &lt; 0.01), memantine (decreased 47.8% at 1 μM, P = 0.0039 and 81.9% at 1 mM, P &lt; 0.001), simvastatin (decreased 85.3% at 0.01 μM, P &lt; 0.001 and 84.8% at 0.05 μM , P &lt; 0.001) or epicatechin (83.6% decrease, P &lt; 0.05), Z-IETD-FMK (68.1% decrease, P &lt; 0.01), and Z-ATAD-FMK (47.7% decrease, P = 0.0017). In contrast, R28 cells exposed to 7kCh continued to have elevated caspase- 3/7, -8, and -12 activities (between 25.7% decrease and 17.5% increase in msi, P &gt; 0.05) regardless of the pretreatment. Conclusion: Several current drugs protect ARPE-19 cells but not R28 cells from 7kChinduced apoptosis, suggesting that a multiple-drug approach is needed to protect both cells types in various retinal diseases

Topline Results From Prospective, Double-masked, Placebo Controlled Phase 2 Clinical Study Evaluating Luminate® (ALG-1001) in Patients with Symptomatic Focal Vitreomacular Adhesion

Purpose : To investigate the safety and efficacy of Luminate (ALG-1001), a synthetic anti-angiogenic and vitreolytic oligopeptide, administered intravitreally in patients with focal vitreomacular adhesion (VMA) or vitreomacular traction (VMT)

Safety and Efficacy of Risuteganib in Intermediate Non-exudative Age-Related Macular Degeneration

Purpose : Risuteganib is a small synthetic peptide that regulates select integrin functions involved in the pathogenesis of dry age-related macular degeneration (AMD). This study evaluated the safety and efficay of risuteganib for the treatment of dry AMD. Methods : Randomized, double-masked, placebo-controlled Phase 2 study in eyes with intermediate dry AMD presenting with best-corrected visual acuity (BCVA) between 20/40-20/200 was conducted across multiple centers in the United States. Patients were randomized to receive either intravitreal 1.0mg risuteganib or sham injection at baseline. At week 16, patients in the risuteganib group received a second dose and the sham group crossed over and receive a single dose of 1.0mg risuteganib. The primary endpoint was the percentage of population with ≥ 8 letters BCVA gain from baseline to week 28 in 1.0mg risuteganib vs baseline to week 12 for sham. Results : Forty-five patients were enrolled in the study. At baseline, mean patient age was 78.8 and 75.9 years and mean baseline BCVA was 67.1 and 64.4 letters in the sham and risuteganib groups, respectively. The primary endpoint was met; 48% of patients in the risuteganib group at week 28 and 7% of patients in the sham group at week 12 gained > 8 letters from baseline (p=0.013). Of the risuteganib treated patients, 20% gained > 15 letters at week 28; no patients in the sham group at week 12 had this gain. On a post-hoc masked analysis by 2 independent reading centers, greater outer retinal and photoreceptor thickness and volume and smaller ellipsoid zone defect area in the central 1 mm zone at baseline were associated with increased BCVA response to risuteganib. Risuteganib demonstrated a good safety profile in this study. Conclusions : Risuteganib showed significant benefit over sham in patients with dry AMD with respect to proportion of patients gaining > 8 letters of BCVA from baseline. Furthermore, post hoc analysis provides preliminary insights into baseline anatomic features that may help to determine likelihood of BCVA response to risuteganib. These findings will be confirmed in an upcoming larger trial