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As the mammalian central nervous system matures, its regenerative ability decreases, leading to incomplete or non‐recovery from the neurodegenerative diseases and central nervous system insults that we are increasingly facing in our aging world population. Current neuroregenerative research is largely directed toward identifying the molecular and cellular players that underlie central nervous system repair, yet it repeatedly ignores the aging context in which many of these diseases appear. Using an optic nerve crush model in a novel biogerontology model, that is, the short‐living African turquoise killifish, the impact of aging on injury‐induced optic nerve repair was investigated. This work reveals an age‐related decline in axonal regeneration in female killifish, with different phases of the repair process being affected depending on the age. Interestingly, as in mammals, both a reduced intrinsic growth potential and a non‐supportive cellular environment seem to lie at the basis of this impairment. Overall, we introduce the killifish visual system and its age‐dependent regenerative ability as a model to identify new targets for neurorepair in non‐regenerating individuals, thereby also considering the effects of aging on neurorepair. [ABSTRACT FROM AUTHOR]

Purpose: Previous reports have yielded conflicting data on the activity of bevacizumab (Avastin), a recombinant humanized monoclonal antibody against VEGF-A, in the mouse. The current study was designed to further explore the use of this VEGF inhibitor in various murine models of ocular diseases and compare it to the widely used murine anti-VEGF-R2 neutralizing antibody (DC101). Methods: Murine models of laser-induced choroidal neovascularization (CNV), oxygen-induced retinopathy (OIR) and glaucoma filtration surgery (GFS) were used to investigate the effect of bevacizumab. Mice either received an intravitreal (CNV-OIR) or subconjunctival (GFS) injection. In all models, they were divided in two groups ( n = 10 per group). In the first group, one eye was injected with bevacizumab (1 µl; 25 µg) and the other eye was used as a negative control and received an injection of NaCl (1 µl; 0.9%). In the second group, one eye was injected with DC101 (1 µl; 6.2 µg), whereas an isotype-matched control antibody (1C8; 4.8 µg) was administered in the contralateral eye. Treatment outcome was studied by clinical investigation (GFS) and immunohistological analysis of angiogenesis (CD31/FITC-dextran/H&E) and fibrosis (Sirius Red). Results: Analysis of blood vessel density (CNV) and blood vessel growth (OIR) showed a comparable decrease after intravitreal administration of bevacizumab or DC101. Furthermore, in the mouse model of GFS, clinical investigation of the bleb and a CD31 staining on sections demonstrated that subconjunctival injection of both antibodies similarly improved the surgical outcome (bleb area and survival) by reducing angiogenesis. Moreover, morphometric analysis after Sirius Red staining showed a comparable reduction in collagen deposition after administration of the inhibitors. Conclusion: Our findings consistently demonstrate that bevacizumab is as effective as the murine anti-VEGF-R2 antibody (DC101) in mouse models of CNV, OIR and GFS, thus confirming its suitability for translational ophthalmological research. [ABSTRACT FROM AUTHOR]

Purpose: Pentosan polysulfate sodium (PPS; Elmiron) is a FDA-approved heparanase inhibitor for the treatment of bladder pain and interstitial cystitis. The chronic use of PPS has been associated with a novel pigmentary maculopathy, associated with discrete vitelliform deposits that exhibit hyperfluorescence, macular hyper-pigmentary spots, and foci of nodular RPE enlargement. Therefore, this study aimed to investigate the retinal morphology of heparanase knockout mice., Material and Methods: The retinal morphology of heparanase knock-out and age-matched control wild type mice of 3-, 9- and 15-weeks old was characterized by means of histological evaluation. Immuno-histological stains for RPE65, F4/80 and Ki67 were performed for investigating the RPE, inflammatory and proliferating cells, respectively., Results: Histological analysis showed no changes in age-matched wild-type controls, whereas the eyes of heparanase null mice were characterized by alterations in RPE and neural retina, as manifest by RPE folds and choroidal thickening, detached RPE cells, thickening of the photoreceptor layer and retinal disorganization. The presence of discrete hyperfluorescent foci, however, was absent. The prevalence of the RPE/choroidal changes or protrusions seemed to progress over time and were correlated with more RPE65 signal rather than influx of F4/80- or Ki67-positive cells. These results indicate that the subretinal alterations were mostly RPE driven, without influx of inflammatory or proliferating cells., Conclusions: Our results indicate that heparanase deficiency in the mice leads to RPE folds, choroidal thickening, and retinal disorganization. The presence of discrete hyperfluorescent foci, a key characteristic of the human disease, was not observed. However, it can be concluded that some of the observations in mice are similar to those seen after chronic use of PPS in humans. These findings indicate that the toxicity observed in the presence of heparanase inhibitors is target-related and will preclude the clinical use of heparanase inhibition as a therapeutic intervention.

Purpose: Rho kinase (ROCK) is associated with VEGF-driven angiogenesis, as well as with inflammation and fibrosis. Therefore, the effect of AMA0428, a novel ROCK inhibitor, was studied in these processes, which highly contribute to the pathogenesis of neovascular AMD., Methods: The effect of AMA0428 (0.5-5.0 μM) on human umbilical vein endothelial cells (HUVECs), human brain microvascular endothelial cells (HBMECs), and human brain microvascular pericytes (HBVPs) was determined using cell viability (WST-1), apoptosis (caspase 3/7), and migration (scratch and under-agarose) assays. The in vivo response was investigated using a laser-induced choroidal neovascularization (CNV) mouse model, in which intravitreal injections of AMA0428, murine anti-VEGF-R2 mAb (DC101), or placebo was given. Outcome was assessed by analysis of inflammation (CD45), angiogenesis (FITC-dextran), vessel leakage (Texas Red-conjugated Dextran and FITC-labeled lectin) and fibrosis (Sirius Red/Collagen I)., Results: The AMA0428 dose-dependently reduced proliferation and VEGF-induced migration of HUVEC and HBMEC (P < 0.05). No significant effect was seen on HBVP proliferation; however, migration and pericyte recruitment were enhanced (P < 0.05) by AMA0428 administration. There was no apoptosis induction. The AMA0428 significantly reduced CNV and vessel leakage 2 weeks after laser treatment, comparable to DC101. In addition, AMA0428 inhibited inflammation on day 5 by 42% (P < 0.05) and collagen deposition on day 30 by 43% (P < 0. 05), whereas DC101 had no effect on inflammation nor on fibrosis., Conclusions: The results suggest that targeting ROCK with AMA0428 not only reduces neoangiogenesis, but also blocks inflammation and fibrosis (contrary to VEGF suppression). These results point to a potential therapeutic benefit of ROCK inhibition in neovascular AMD., (Copyright 2015 The Association for Research in Vision and Ophthalmology, Inc.)

Glaucoma is a neurodegenerative disease and is the second most important cause of irreversible blindness. Filtration surgery remains the most effective therapy to reduce intraocular pressure in glaucoma patients. The main determinant of long-term surgical success is the healing response. Excessive postoperative wound healing with subsequent fibrosis may lead to obstruction of the created channel which frequently results in early surgical failure and consequent progression of visual field loss. Preoperative use of antimitotics, such as mitomycin-C and 5-fluorouracyl, effectively improves surgery outcome. However, the use of these nonspecific antiproliferative agents can be associated with severe side effects. This review provides an overview of the most important efforts that have been made to explore novel, more specific, and safer agents to prevent glaucoma filtration failure and improve surgery outcome., (© 2015 Elsevier B.V. All rights reserved.)