Visible light affects mitochondrial function and induces neuronal death in retinal cell cultures

AbstractThe aim of this study was to provide “proof of principle” for the hypothesis that light would have a detrimental influence on ganglion cells in certain situations, like in glaucoma, by directly impinging on the many mitochondria in their axons within the globe. In this study primary rat retinal cultures and freshly isolated liver mitochondria were exposed to light (400–760nm; 500–4000lux) as entering the eye. For culture assessment, 3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 4-[3-(-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetzolio]-1,3-benzene disulfonate (WST-1) reduction assays were used to assess cell and mitochondrial viability, respectively. Furthermore, cultures were stained for reactive oxygen species (ROS), DNA breakdown, numbers of GABA-immunoreactive (IR) cells and caspase-3 content to provide information concerning the effect of light on neuronal survival. Uptake of 3H-GABA by autoradiography was also used, to assess the effects of light on the energy status of neurons. Light, in an intensity-dependent and trolox-inhibitable manner, reduced cell viability, affected mitochondrial function, increased the number of TUNEL-positive cells, decreased the numbers of GABA-IR neurons and enhanced labelling for ROS. These effects were all exacerbated by the absence of serum. There was also an increased caspase-3 protein content and a reduction of 3H-GABA uptake in light- compared with dark-treated cultures. These findings support the hypothesis that light can affect mitochondria which could lead to neuronal apoptosis if the energetic status of these neurons is already compromised

Evaluation of the effect of intravitreal ranibizumab injections in patients with neovascular age related macular degeneration on retinal nerve fiber layer thickness using optical coherence tomography

PURPOSE: To evaluate the effect of repeated intravitreal ranibizumab injections for neovascular age related macular degeneration (nAMD) on the retinal nerve fiber layer (RNFL) thickness using optical coherence tomography. DESIGN: A prospective observational cohort study of patients with nAMD. METHODS: Thirty eyes of 30 patients with nAMD were selected. All patients received three ranibizumab injections and underwent scans using the fast RNFL thickness protocol (Stratus optical coherence tomography) before starting the first injection and 1 month after the third injection. The RNFL thickness measurements prior to the injections and after the third injection were used for the analysis. We also evaluated the effect of the lens status as well as the type of choroidal neovascular membrane on RNFL thickness measurements pre- and post-injection. Pre- and post-injection average and individual quadrant RNFL thickness were measured and statistically analyzed. RESULTS: The mean (± standard deviation) pre-injection RNFL thickness was 90.8±18. The mean (± standard deviation) post-injection RNFL thickness was 91.03±15. The pre- and post-injection values of the mean RNFL thickness were not statistically significant. Likewise, the pre- and post-injection values for RNFL thickness in the different quadrants were not statistically significant. There was no statistical significance for the lens status or the type of choroidal neovascular membrane on the RNFL thickness. CONCLUSION: Repeated ranibizumab injections in nAMD appear to have no harmful effect on the RNFL thickness in the short term, in spite of the proven neurotrophic effect of vascular endothelial growth factor. Nevertheless, the safety profile of ranibizumab injections in nAMD needs to be further evaluated in a large multicenter trial with special emphasis on the long-term effects on the retina and optic nerve

The Role of Mitophagy in Glaucomatous Neurodegeneration

settingsOrder Article Reprints Open AccessReview The Role of Mitophagy in Glaucomatous Neurodegeneration by Dimitrios Stavropoulos 1,2,Manjot K. Grewal 3,4,Bledi Petriti 3,5,Kai-Yin Chau 5ORCID,Christopher J. Hammond 6,7,David F. Garway-Heath 3ORCID andGerassimos Lascaratos 1,6,*ORCID 1 Department of Ophthalmology, King’s College Hospital, London SE5 9RS, UK 2 Department of Ophthalmology, 417 Veterans Army Hospital (NIMTS), 11521 Athens, Greece 3 NIHR Biomedical Research Center, Moorfields Eye Hospital and UCL Institute of Ophthalmology, London EC1V 9EL, UK 4 Division of Optometry and Visual Science, School of Health Sciences, City, University of London, London EC1V 0HB, UK 5 Department of Clinical & Movement Neurosciences, UCL Queens Square Institute of Neurology, London NW3 2PF, UK 6 Section of Ophthalmology, School of Life Course Sciences, King’s College London, London SE1 7EH, UK 7 Department of Ophthalmology, St Thomas’ Hospital, London SE1 7EH, UK * Author to whom correspondence should be addressed. Cells 2023, 12(15), 1969; https://doi.org/10.3390/cells12151969 Received: 3 June 2023 / Revised: 15 July 2023 / Accepted: 19 July 2023 / Published: 30 July 2023 (This article belongs to the Special Issue Recent Research on the Role of Mitochondria in Neurodegeneration) Download Browse Figures Review Reports Versions Notes Abstract This review aims to provide a better understanding of the emerging role of mitophagy in glaucomatous neurodegeneration, which is the primary cause of irreversible blindness worldwide. Increasing evidence from genetic and other experimental studies suggests that mitophagy-related genes are implicated in the pathogenesis of glaucoma in various populations. The association between polymorphisms in these genes and increased risk of glaucoma is presented. Reduction in intraocular pressure (IOP) is currently the only modifiable risk factor for glaucoma, while clinical trials highlight the inadequacy of IOP-lowering therapeutic approaches to prevent sight loss in many glaucoma patients. Mitochondrial dysfunction is thought to increase the susceptibility of retinal ganglion cells (RGCs) to other risk factors and is implicated in glaucomatous degeneration. Mitophagy holds a vital role in mitochondrial quality control processes, and the current review explores the mitophagy-related pathways which may be linked to glaucoma and their therapeutic potential

Relationships between retinal layer thickness and brain volumes in the UK Biobank cohort

Background and purpose: Current methods to diagnose neurodegenerative diseases are costly and invasive. Retinal neuroanatomy may be a biomarker for more neurodegenerative processes and can be quantified in vivo using optical coherence tomography (OCT), which is inexpensive and noninvasive. We examined the association of neuroretinal morphology with brain MRI image-derived phenotypes (IDPs) in a large cohort of healthy older people. Methods: UK Biobank participants aged 40 to 69 years old underwent comprehensive examinations including ophthalmic and brain imaging assessments. Macular retinal nerve fibre layer (mRNFL), macular ganglion cell-inner plexiform layer (mGCIPL), macular ganglion cell complex (mGCC) and total macular thicknesses were obtained from OCT. Magnetic resonance imaging (MRI) IDPs assessed included total brain, grey matter, white matter and hippocampal volume. Multivariable linear regression models were used to evaluate associations between retinal layers thickness and brain MRI IDPs, adjusting for demographic factors and vascular risk factors. Results: A total of 2131 participants (mean age 55 years; 51% women) with both gradable OCT images and brain imaging assessments were included. In multivariable regression analysis, thinner mGCIPL, mGCC and total macular thickness were all significantly associated with smaller total brain (p < 0.001), grey matter and white matter volume (p < 0.01), and grey matter volume in the occipital pole (p < 0.05). Thinner mGCC and total macular thicknesses were associated with smaller hippocampal volume (p < 0.02). No association was found between mRNFL and the MRI IDPs. Conclusions: Markers of retinal neurodegeneration are associated with smaller brain volumes. Our findings suggest that retinal structure may be a biomarker providing information about important brain structure in healthy older adults

Latanoprost for open-angle glaucoma (UKGTS): a randomised, multicentre, placebo-controlled trial

Background: Treatments for open-angle glaucoma aim to prevent vision loss through lowering of intraocular pressure, but to our knowledge no placebo-controlled trials have assessed visual function preservation, and the observation periods of previous (unmasked) trials have typically been at least 5 years. We assessed vision preservation in patients given latanoprost compared with those given placebo. Methods: In this randomised, triple-masked, placebo-controlled trial, we enrolled patients with newly diagnosed open-angle glaucoma at ten UK centres (tertiary referral centres, teaching hospitals, and district general hospitals). Eligible patients were randomly allocated (1:1) with a website-generated randomisation schedule, stratified by centre and with a permuted block design, to receive either latanoprost 0·005% (intervention group) or placebo (control group) eye drops. Drops were administered from identical bottles, once a day, to both eyes. The primary outcome was time to visual field deterioration within 24 months. Analyses were done in all individuals with follow-up data. The Data and Safety Monitoring Committee (DSMC) recommended stopping the trial on Jan 6, 2011 (last patient visit July, 2011), after an interim analysis, and suggested a change in primary outcome from the difference in proportions of patients with incident progression between groups to time to visual field deterioration within 24 months. This trial is registered, number ISRCTN96423140. Findings: We enrolled 516 individuals between Dec 1, 2006, and March 16, 2010. Baseline mean intraocular pressure was 19·6 mm Hg (SD 4·6) in 258 patients in the latanoprost group and 20·1 mm Hg (4·8) in 258 controls. At 24 months, mean reduction in intraocular pressure was 3·8 mm Hg (4·0) in 231 patients assessed in the latanoprost group and 0·9 mm Hg (3·8) in 230 patients assessed in the placebo group. Visual field preservation was significantly longer in the latanoprost group than in the placebo group: adjusted hazard ratio (HR) 0·44 (95% CI 0·28–0·69; p=0·0003). We noted 18 serious adverse events, none attributable to the study drug. Interpretation: This is the first randomised placebo-controlled trial to show preservation of the visual field with an intraocular-pressure-lowering drug in patients with open-angle glaucoma. The study design enabled significant differences in vision to be assessed in a relatively short observation period

Alcoholic liver disease and bilateral multifocal central serous retinopathy:a case report

INTRODUCTION: We present a unique case of a patient with bilateral, multifocal central serous retinopathy in a patient with alcoholic liver disease. CASE PRESENTATION: A 58-year-old Caucasian man with alcoholic liver disease, liver cirrhosis and ascites presented to the eye clinic. The ophthalmoscopic examination of both eyes revealed a symmetrical pattern of variably sized, slightly yellowish, translucent, raised lesions throughout the fundi which were confirmed to be caused by multifocal central serous retinopathy after optical coherence tomography and autofluoresence tests. CONCLUSION: This case highlights the possible link between central serous retinopathy and end-stage liver disease, with potential implications for the pathogenesis of central serous retinopathy in these patients

Associations with photoreceptor thickness measures in the UK Biobank.

Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40-69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness

Investigation of associations between retinal microvascular parameters and albuminuria in UK Biobank: a cross-sectional case-control study.

BACKGROUND: Associations between microvascular variation and chronic kidney disease (CKD) have been reported previously. Non-invasive retinal fundus imaging enables evaluation of the microvascular network and may offer insight to systemic risk associated with CKD. METHODS: Retinal microvascular parameters (fractal dimension [FD] - a measure of the complexity of the vascular network, tortuosity, and retinal arteriolar and venular calibre) were quantified from macula-centred fundus images using the Vessel Assessment and Measurement Platform for Images of the REtina (VAMPIRE) version 3.1 (VAMPIRE group, Universities of Dundee and Edinburgh, Scotland) and assessed for associations with renal damage in a case-control study nested within the multi-centre UK Biobank cohort study. Participants were designated cases or controls based on urinary albumin to creatinine ratio (ACR) thresholds. Participants with ACR ≥ 3 mg/mmol (ACR stages A2-A3) were characterised as cases, and those with an ACR < 3 mg/mmol (ACR stage A1) were categorised as controls. Participants were matched on age, sex and ethnic background. RESULTS: Lower FD (less extensive microvascular branching) was associated with a small increase in odds of albuminuria independent of blood pressure, diabetes and other potential confounding variables (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.03-1.34 for arterioles and OR 1.24, CI 1.05-1.47 for venules). Measures of tortuosity or retinal arteriolar and venular calibre were not significantly associated with ACR. CONCLUSIONS: This study supports previously reported associations between retinal microvascular FD and other metabolic disturbances affecting the systemic vasculature. The association between retinal microvascular FD and albuminuria, independent of diabetes and blood pressure, may represent a useful indicator of systemic vascular damage associated with albuminuria

Automated quantification of retinal vessel morphometry in the UK Biobank Cohort

The following topics are dealt with: feature extraction; learning (artificial intelligence); image classification; image segmentation; computer vision; object detection; feedforward neural nets; image colour analysis; image representation; medical image processing