A Fair Assessment of Evaluation Tools for the Murine Microbead Occlusion Model of Glaucoma.
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ABSTRACT:
SUBMITTER: Claes M
PROVIDER: S-EPMC8199180 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). The disease causes vision loss through the degeneration of retinal ganglion cell neurons and their axons in the optic nerve. Using an inducible model of glaucoma, we elevated IOP in the squirrel monkey (Saimiri boliviensis) using intracameral injection of 35 μm polystyrene microbeads and measured common pathogenic outcomes in the optic projection. A 42% elevation in IOP over 28 weeks reduced anterograde transport of fluorescently-labeled cholera toxin beta from retina to the lateral geniculate nucleus (60% decrease), and to the superior colliculus (49% decrease). Pressure also reduced survival of ganglion cellaxons in the optic nerve by 22%. The same elevation caused upregulation of proteins associated with glaucomatous neurodegeneration in the retina and optic nerve, including complement 1q, interleukin 6, and brain-derived neurotrophic factor. That axon degeneration in the nerve lagged deficits in anterograde transport is consistent with progression in rodent models, while the observed protein changes also occur in tissue from human glaucoma patients. Thus, microbead occlusion in a non-human primate with a visual system similar to our own represents an attractive model to investigate neurodegenerative mechanisms and therapeutic interventions for glaucoma.
| S-EPMC6689098 | biostudies-literature
Project description:PurposeA major challenge in glaucoma research is the lack of reproducible animal models of RGC and optic nerve damage, the characteristic features of this condition. We therefore examined the glaucomatous responses of two different rat strains, the Brown Norway (BN) and Lister Hooded (LH) rats, to high intraocular pressure (IOP) induced by injection of magnetic beads into the anterior chamber.MethodsMagnetic microsphere suspensions (20 µl of 5-20 mg/ml) were injected into the anterior chamber of BN (n = 9) or LH (N = 15) rats. Animals from each strain were divided into three groups, each receiving a different dose of microspheres. IOP was measured over 4 weeks using a rebound tonometer. Retinal ganglion cell (RGC) damage and function were assessed using scotopic electroretinograms (ERGs), retinal flatmounts and optic nerve histology. ANOVA and Student's t-tests were used to analyse the data.ResultsA significant elevation in IOP was observed in BN rats receiving injections of 20 mg (37.18 ± 12.28 mmHg) or 10 mg microspheres/ml (36.95 ± 13.63 mmHg) when compared with controls (19.63 ± 4.29 mmHg) (p < .001) over 2 weeks. This correlated with a significant impairment of RGC function, as determined by scotopic ERG (p < .001), reduction in axon number (p < .05) and lower RGC density (P < .05) in animals receiving 20 mg or 10 mg microspheres/ml as compared with controls. LH rats receiving similar microsphere doses showed reduced scotopic ERG function (p < .001) after 2 weeks. No changes in IOP was seen in this strain, although a reduction in axon density was observed in optic nerve cross-sections (p < .05). Initial changes in IOP and ERG responses observed in BN rats remained unchanged for a duration of 7 weeks. In LH animals, ERG responses were decreased at 1-2 weeks and returned to control levels after 5 weeks.ConclusionsAlthough this model was easily reproducible in BN rats, the phenotype of injury observed in LH rats was very different from that observed in BN animals. We suggest that differences in the glaucomatous response observed in these two strains may be ascribed to anatomical and physiological differences and merits further investigation.
| S-EPMC8025805 | biostudies-literature
Project description:The purpose of this study was to utilize RNAseq to determine if there are changes in ion channel mRNA expression in the retina of C57BL/6 mice subjected to the Microbead Occlusion Model. Whole retina was isolated from 2 month old mice that received intracameral injections of either saline or 15-um-diameter microbeads. Total RNA was isolated from the retinas and subjected to RNA sequencing using Illumina HiSeq 2500. Fold change in mRNA expression was compared between saline- and microbead-injected samples. We then analyzed these data for changes in expression of potassium channels, such as tandem-pore domain K+ channels, inwardly rectifying K+ channels, and the Na+/K+-ATPase.
2018-10-01 | GSE116915 | GEO
Project description:The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer’s disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here we find that in two mouse glaucoma models and in human glaucomatous retinas, microglia transition to a neurodegenerative (MGnD) phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3). Mice in which Apoe was targeted in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss despite elevated intraocular pressure (IOP). Similar to Apoe–/– retinal microglia, APOE4 microglia did not upregulate MGnD genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma, and that the APOE-Galectin-3 signaling pathway can be targeted to treat this blinding disease.
2022-08-16 | GSE192508 | GEO
Project description:PurposeTo characterize the microbead-induced ocular hypertension (OHT) mouse model and investigate its potential use for preclinical screening and evaluation of ocular hypotensive agents, we tested the model's responses to major antiglaucoma drugs.MethodsAdult C57BL/6J mice were induced to develop OHT unilaterally by intracameral injection of microbeads. The effects of the most commonly used ocular hypotensive drugs, including timolol, brimonidine, brinzolamide, pilocarpine, and latanoprost, on IOP and glaucomatous neural damage were evaluated. Degeneration of retinal ganglion cells (RGCs) and optic nerve axons were quantitatively assessed using immunofluorescence labeling and histochemistry. Thickness of the ganglion cell complex (GCC) was also assessed with spectral-domain optical coherence tomography (SD-OCT).ResultsA microbead-induced OHT model promptly responded to drugs, such as timolol, brimonidine, and brinzolamide, that lower IOP through suppressing aqueous humor production and showed improved RGC and axon survival as compared to vehicle controls. Accordingly, SD-OCT detected significantly less reduction of GCC thickness in mice treated with all three aqueous production suppressants as compared to the vehicle contol-treated group. In contrast, drugs that increase aqueous outflow, such as pilocarpine and latanoprost, failed to decrease IOP in the microbead-induced OHT mice.ConclusionsMicrobead-induced OHT mice carry dysfunctional aqueous outflow facility and therefore offer a unique model that allows selective screening of aqueous production suppressant antiglaucoma drugs or for studying the mechanisms regulating aqueous humor production. Our data set the stage for using GCC thickness assessed by SD-OCT as an imaging biomarker for noninvasive tracking of neuronal benefits of glaucoma therapy in this model.
| S-EPMC3390181 | biostudies-literature
Project description:IGFBPL1 deficiency leads to progressive retinal neuron loss and phosphorylated Tau accumulation in the brain. To investigate the role of IGFBL1 in retina microglia homestasis and function. Total immune cells were sorted from microbead (MB)-induced glaucoma mice and glucoma mice treated with recombinant Igfbpl1 protein for single cell RNAseq analysis by 10X genomics technology.
2023-07-26 | GSE226456 | GEO
Project description:Stoffenmanager®v4.5 and Advanced REACH Tool (ART) v1.5, two higher tier exposure assessment tools for use under REACH, were evaluated by determining accuracy and robustness. A total of 282 exposure measurements from 51 exposure situations (ESs) were collected and categorized by exposure category. In this study, only the results of liquids with vapor pressure (VP) > 10 Pa category having a sufficient number of exposure measurements (n = 251 with 42 ESs) were utilized. In addition, the results were presented by handling/activity description and input parameters for the same exposure category. It should be noted that the performance results of Stoffenmanager and ART in this study cannot be directly compared for some ESs because ART allows a combination of up to four subtasks (and nonexposed periods) to be included, whereas the database for Stoffenmanager, separately developed under the permission of the legal owner of Stoffenmanager, permits the use of only one task to predict exposure estimates. Thus, it would be most appropriate to compare full-shift measurements against ART predictions (full shift including nonexposed periods) and task-based measurements against task-based Stoffenmanager predictions. For liquids with VP > 10 Pa category, Stoffenmanager®v4.5 appeared to be reasonably accurate and robust when predicting exposures [percentage of measurements exceeding the tool's 90th percentile estimate (%M > T) was 15%]. Areas that could potentially be improved include ESs involving the task of handling of liquids on large surfaces or large work pieces, allocation of high and medium VP inputs, and absence of local exhaust ventilation input. Although the ART's median predictions appeared to be reasonably accurate for liquids with VP > 10 Pa, the %M > T for the 90th percentile estimates was 41%, indicating that variance in exposure levels is underestimated by ART. The %M > T using the estimates of the upper value of 90% confidence interval (CI) of the 90th percentile estimate (UCI90) was considerably reduced to 18% for liquids with VP > 10 Pa. On the basis of this observation, users might be to consider using the upper limit value of 90% CI of the 90th percentile estimate for predicting reasonable worst case situations. Nevertheless, for some activities and input parameters, ART still shows areas to be improved. Hence, it is suggested that ART developers review the assumptions in relation to exposure variability within the tool, toward improving the tool performance in estimating percentile exposure levels. In addition, for both tools, only some handling/activity descriptions and input parameters were considered. Thus, further validation studies are still necessary.
| S-EPMC6939284 | biostudies-literature
Project description:Tier 1 occupational exposure assessment tools recommended for use under the Registration, Evaluation, Authorization, and restriction of CHemicals (REACH) were evaluated using newly collected measurement data. Evaluated tools included the ECETOC TRAv2 and TRAv3, MEASEv1.02.01, and EMKG-EXPO-TOOL. Fifty-three exposure situations (ESs) based on tasks/chemicals were developed from National Institute for Occupational Safety and Health field surveys. During the field surveys, high quality contextual information required for evaluating the tools was also collected. For each ES, applicable tools were then used to generate exposure estimates using a consensus approach. Among 53 ESs, only those related to an exposure category of liquids with vapor pressure (VP) > 10 Pa had sufficient numbers of exposure measurements (42 ESs with n = 251 for TRAv2 and TRAv3 and 40 ESs with n = 243 for EMKG-EXPO-TOOL) to be considered in detail. The results for other exposure categories (aqueous solutions, liquids with VP ≤ 10 Pa, metal processing, powders, and solid objects) had insufficient measurement to allow detailed analyses (results listed in the Supplementary File). Overall, EMKG-EXPO-TOOL generated more conservative results than TRAv2 and TRAv3 for liquids with high VP. This finding is at least partly due to the fact that the EMKG-EXPO-TOOL only considers pure substances and not mixtures of chemical agents. For 34 out of 40 ESs available for chemicals with VP > 10 Pa, the liquid was a mixture rather than a pure substance. TRAv3 was less conservative than TRAv2, probably due to additional refinement of some input parameters. The percentages of exposure measurement results exceeding the corresponding tool estimates for liquids with VP > 10 Pa by process category and by input parameters were always higher for TRAv3 compared to those for TRAv2. Although the conclusions of this study are limited to liquids with VP > 10 Pa and few process categories, this study utilized the most transparent contextual information compared to previous studies, reducing uncertainty from assumptions for unknown input parameters. A further validation is recommended by collecting sufficient exposure data covering other exposure categories and all process categories under REACH.
| S-EPMC6939290 | biostudies-literature
Project description:RNAseq quantitative analysis of ion channel mRNA expression in microbead occlusion model
| PRJNA480596 | ENA
Project description:PurposeTo determine if retinal ganglion cell (RGC) axon loss in experimental mouse glaucoma is uniform in the optic nerve.MethodsExperimental glaucoma was induced for 6 weeks with a microbead injection model in CD1 (n = 78) and C57BL/6 (B6, n = 68) mice. From epoxy-embedded sections of optic nerve 1 to 2 mm posterior to the globe, total nerve area and regional axon density (axons/1600 μm2) were measured in superior, inferior, nasal, and temporal zones.ResultsControl eyes of CD1 mice have higher axon density and more total RGCs than control B6 mice eyes. There were no significant differences in control regional axon density in all mice or by strain (all P > 0.2, mixed model). Exposure to elevated IOP caused loss of RGC in both strains. In CD1 mice, axon density declined without significant loss of nerve area, while B6 mice had less density loss, but greater decrease in nerve area. Axon density loss in glaucoma eyes was not significantly greater in any region in either mouse strain (both P > 0.2, mixed model). In moderately damaged CD1 glaucoma eyes, and CD1 eyes with the greatest IOP elevation exposure, density loss differed by region (P = 0.05, P = 0.03, mixed model) with the greatest loss in the temporal and superior regions, while in severely injured B6 nerves superior loss was greater than inferior loss (P = 0.01, mixed model, Bonferroni corrected).ConclusionsThere was selectively greater loss of superior and temporal optic nerve axons of RGCs in mouse glaucoma at certain stages of damage. Differences in nerve area change suggest non-RGC responses differ between mouse strains.
| S-EPMC5455173 | biostudies-literature