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Investigative Ophthalmology and Visual Science

Muller glial cells span the entire thickness of the tissue, and ensheath all retinal neurons, in vertebrate retinae of all species. This morphological relationship is reflected by a multitude of functional interactions between neurons and Muller cells, including a 'metabolic symbiosis' and the processing of visual information. Muller cells are also responsible for the maintenance of the homeostasis of the retinal extracellular milieu (ions, water, neurotransmitter molecules, and pH). In vascularized retinae, Muller cells may also be involved in the control of angiogenesis, and the regulation of retinal blood flow. Virtually every disease of the retina is associated with a reactive Muller cell gliosis which, on the one hand, supports the survival of retinal neurons but, on the other hand, may accelerate the progress of neuronal degeneration: Muller cells protect neurons via a release of neurotrophic factors, the uptake and degradation of the excitotoxin, glutamate, and the secretion of the antioxidant, glutathione. However, gliotic Muller cells display a dysregulation of various neuron-supportive functions. This contributes to a disturbance of retinal glutamate metabolism and ion homeostasis, and causes the development of retinal edema and neuronal cell death. Moreover, there are diseases evoking a primary Muller cell insufficiency, such as hepatic retinopathy and certain forms of glaucoma. Any impairment of supportive functions of Muller cells, primary or secondary, must cause and/or aggravate a dysfunction and loss of neurons, by increasing the susceptibility of neurons to stressful stimuli in the diseased retina. On the contrary, Muller cells may be used in the future for novel therapeutic strategies to protect neurons against apoptosis (somatic gene therapy), or to differentiate retinal neurons from Muller/stem cells. Meanwhile, a proper understanding of the gliotic responses of Muller cells in the diseased retina, and of their protective vs. detrimental effects, is essential for the development of efficient therapeutic strategies that use and stimulate the neuron-supportive/protective-and prevent the destructive-mechanisms of gliosis.

https://www.springer.com/cda/content/document/productFlyer/productFlyer_978-1-4419-1671-6.pdf?SGWID=0-0-1297-173938007-0

Müller Cells in the Healthy and Diseased Retina

Purpose. To characterize the intrinsic fluorescence (autofluorescence) of the human ocularfundus with regard to its excitation and emission spectra, age relationship, retinal location,and topography, and to identify the dominant fluorophore among the fundus layers.Methods. Using a novel fundus spectrophotometer, fluorescence measurements were made at7° temporal to the fovea and at the fovea in 30 normal subjects and in 3 selected patients.Topographic measurements were made in 3 subjects. Ex vivo measurements of fluorescenceof human retinal pigment epithelium (RPE) were obtained and compared to in vivo data.Results. Fundus fluorescence reveals a broad band of emission between 500 and 750 nm, amaximum of approximately 630 nm, and optimal excitation of approximately 510 nm. Exhib-iting a significant increase with age, this fluorescence is highest at 7° to 15° from the fovea,shows a well-defined foveal minimum, and decreases toward the periphery. In vivo fluores-cence spectra are consistent with those obtained ex vivo on human RPE. Measurements withshort wavelength excitation are strongly influenced by ocular media absorption and revealan additional minor fluorophore in the fovea.Conclusions. Spectral characteristics, correlation with age, topographic distribution, and retinallocation between the choriocapillaris and the photoreceptors suggest that the dominantfundus fluorophore is RPE lipofuscin. The mino fluorophorer is probably in the neurosensoryretina but has not been identified. Invest Ophthalmol Vis Sci. 1995;36:718-729.Ajipofuscin is an autofluorescent pigment that accu-mulates in the lysosomes of most aging eukaryoticcells. Intensively studied as a biomarker for cellularaging and as a cumulative index of oxidative damage,mounting evidence across the biologic spectrum indi-cates that lipofuscin may play an important role incellular aging and disease.In the human retinal pigment epithelium (RPE),lipofuscin accumulates as a byproduct of phagocytosisof photoreceptor outer segments. In advanced age,lipofuscin is a major constituent of the RPE cell be-

In Vivo Fluorescence of the Ocular Fundus Exhibits Retinal Pigment Epithelium Lipofuscin Characteristics

Lutein, zeaxanthin, and the macular pigment.

The macular region of the primate retina is yellow in color due to the presence of the macular pigment, composed of two dietary xanthophylls, lutein and zeaxanthin, and another xanthophyll, meso-zeaxanthin. The latter is presumably formed from either lutein or zeaxanthin in the retina. By absorbing blue-light, the macular pigment protects the underlying photoreceptor cell layer from light damage, possibly initiated by the formation of reactive oxygen species during a photosensitized reaction. There is ample epidemiological evidence that the amount of macular pigment is inversely associated with the incidence of age-related macular degeneration, an irreversible process that is the major cause of blindness in the elderly. The macular pigment can be increased in primates by either increasing the intake of foods that are rich in lutein and zeaxanthin, such as dark-green leafy vegetables, or by supplementation with lutein or zeaxanthin. Although increasing the intake of lutein or zeaxanthin might prove to be protective against the development of age-related macular degeneration, a causative relationship has yet to be experimentally demonstrated.

Biologic mechanisms of the protective role of lutein and zeaxanthin in the eye.

PURPOSE Macular pigment (MP) may protect against age-related macular degeneration. This study was conducted to determine the extent of changes in the macular pigment density as a consequence of oral supplementation with lutein. A second purpose was to compare two objective measurement techniques. METHODS In the first technique, reflectance maps were made with a scanning laser ophthalmoscope. Digital subtraction of log reflectance maps and comparison between the foveal area and a 14 degrees temporal site provided MP density estimates. In the second technique, spectral fundus reflectance of the fovea was measured with a fundus reflectometer and analyzed with a detailed optical model, to arrive at MP density values. Eight subjects participated in this study. They took 10 mg lutein per day for 12 weeks. Plasma lutein concentration was measured at 4-week intervals. RESULTS After 4 weeks, mean blood level of lutein had increased from 0.18 to 0.90 microM. It stayed at this level throughout the intake period and declined to 0.28 microM 4 weeks after termination. Measurement of the density of MP showed a within-subject variation of 10% with MP maps and 17% with spectral reflectance analysis. MP density showed a mean linear 4-week increase of 5.3% (P: < 0.001) and 4.1% (P: = 0. 022), respectively. CONCLUSIONS Supplementation with lutein significantly increased the density of the MP. Analyzing reflectance maps with a scanning laser ophthalmoscope provided very reliable estimates of MP.

Influence of lutein supplementation on macular pigment, assessed with two objective techniques.

Spectral reflectance of the human eye.

Purpose. To assess the influence of wavelength on retinal light damage in rat with funduscopy and histology and to determine a detailed action spectrum. Methods. Adult Long Evans rats were anesthetized, and small patches of retina were exposed to narrow-band irradiations in the range of 320 to 600 nm using a Tenon arc and Maxwellian view conditions. After 3 days, the retina was examined with funduscopy and prepared for light microscopy. Results. The dose that produced a change just visible in fundo was determined for each wavelength. This threshold dose for funduscopic damage increased monotonically from 0.35 J/cm 2 at 320 nm to 1600 J/cm 2 at 550 nm. At 600 nm, exposure of more than 3000 J/cm 2 did not cause funduscopic damage. Morphologic changes in retinas exposed to threshold doses at wavelengths from 320 to 440 nm were similar and consisted of pyknosis of photorecep tors. Retinas exposed to threshold doses of 470 to 550 nm had different morphologic appearances. Retinal pigment epithelial cells were swollen, and their melanin had lost the characteristic apical distribution. Some pyknosis was found in photoreceptors. Conclusions. Damage sensitivity in rat increases enormously from visible to ultraviolet wavelengths. Compelling evidence is presented that two morphologically distinct types of damage occur in the rat retina, depending on the wavelength. Because two types also have been described in monkey, a remarkable similarity seems to exist across species

Ultraviolet and green light cause different types of damage in rat retina.

AIM—To assess the retinal phototoxicity hazards of and to provide safety margins for endoillumination during vitrectomy.
METHODS—The absolute power and spectral distribution from various light sources and filter combinations that are commercially available for vitreous surgery were measured. The maximal exposure times based on the ICNIRP safety guidelines for photochemical and thermal injury of the aphakic eye were calculated. Additionally, the effect of various measures that reduce the risk of phototoxicity was evaluated.
RESULTS—Measurements of the spectrum and energy indicated that the ICNIRP safety guidelines for photochemical retinal damage are exceeded within 1 minute for nine out of 10 combinations tested. With an additional 475 nm long pass filter, light levels below 10 mW, and a distance from light probe to retina of at least 10 mm, the allowable exposure time can be increased up to 13 minutes. Thermal damage can be anticipated when the light probe touches the retina.
CONCLUSION—Commercially available light sources for endoillumination during vitrectomy are not safe with respect to photochemical retinal damage. Even with maximal precautions macular phototoxic damage remains a factual danger during vitrectomy.

https://bjo.bmj.com/content/bjophthalmol/84/12/1372.full.pdf

Endoillumination during vitrectomy and phototoxicity thresholds.

We investigated foveal cone photopigment kinetics by retinal densitometry in 34 eyes of 29 healthy subjects with clear optical media and good visual acuity, ranging in age from 39 to 79 years. Our aim was to assess possible senile disturbances of foveal cones. To assess the effects of ocular straylight, we measured not only in subjects with a clear crystalline lens, but also in pseudophakia and aphakia. In a limited number of subjects color vision was assessed with a Nagel anomaloscope; no systematic changes with age were found. A significant decrease in two-way density and in time constant of regeneration was found to occur only after age 60, with large individual variations. There was no indication that results for subjects with their natural crystalline lens, in aphakia, or in pseudophakia were different. We argue that a reduction in the number of cones with age, rather than an increase in ocular stray light is the most likely explanation of our findings.

D. Van Norren

Papers

Influence of lutein supplementation on macular pigment, assessed with two objective techniques.

Spectral reflectance of the human eye.

Ultraviolet and green light cause different types of damage in rat retina.

Endoillumination during vitrectomy and phototoxicity thresholds.

Density of foveal cone pigments at older age.