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PubMed1996

Myelin basic protein specific T-helper cells induce experimental anterior uveitis.

Immunopathological changes in the eyes were examined in Lewis rats after active and passive induction of experimental autoimmune encephalomyelitis (EAE) with myelin basic proteins (MBP) at various stages of EAE. The onset of anterior uveitis (AU) coincided with hind limb paralysis, but uveitis persisted after clinical signs of EAE had subsided. A mild form of uveitis was characteristic for the majority of rats. The changes within the iris and ciliary body consisted of an accumulation of inflammatory cells lining the anterior surface of iris, the trabecular meshwork, and, in some cases, within the ciliary body and the aqueous humor. A similar histopathological picture was observed when rats were injected with the secondary encephalitogenic determinant for Lewis rats, MBP peptide 87-99. Flow cytometry analysis of T cells from the anterior segment of the inflamed eyes after immunization with MBP revealed the presence of CD4+ cells exclusively expressing V beta 8.2 and OX-40 markers. Our data suggest that MBP are encephalitogenic and uveitogenic in Lewis rats and that the V beta 8.2-positive T cells in the eye represent encephalitogenic T cells. Many of those T cells were distributed in the iris and the anterior chamber. These findings indicate that these MBP-specific T cells may play a critical role in EAE as well as in AU.

Animals↗
PubMed1997

Expression of meltrin-alpha mRNA is not restricted to fusagenic cells.

Meltrin-alpha is a myoblast gene product reported to be required for cell fusion [Yagami-Hiromasa et al. (1995): Nature 377:652-656]. Because Northern blots revealed expression only in muscle and bone, the suggestion was made that meltrin-alpha is expressed exclusively by fusagenic cells in these tissues (myoblast and osteoclast). We studied expression of meltrin-alpha mRNA in a panel of tissues and cell lines using the polymerase chain reaction and found it widely expressed. Meltrin-alpha mRNA was readily detected in the osteoblast, the most abundant cell type in bone. In situ hybridization analysis on sections of neonatal mice revealed high levels of expression in the trabecular meshwork of long bones, the basal regions of the dermis and its underlying mesenchyme. We conclude that expression of meltrin-alpha mRNA is not restricted to fusagenic cells and that, in bone, the osteoblast is the major source.

ADAM Proteins↗
PubMed2006

Proteases in eye development and disease.

The eye is one of the classical systems in developmental biology. Furthermore, diseases of the eye, many of which have a developmental basis, have devastating effects that often result in blindness. Proteases have diverse roles in ocular physiology and pathophysiology. Here, a broad overview is provided of the recent literature pertaining to the involvement of proteases in various aspects of eye development and disease: lens development (focusing on apoptosis and lens fiber cell denucleation and organelle loss) and cataract progression, cornea development and disease, retina development and degeneration, sclera development and myopia, and the trabecular meshwork and glaucoma. Proteases discussed include caspases, calpains, matrix metalloproteases (MMPs), a disintegrin and metalloproteinases (ADAMs) and ADAM with thrombospondin motifs (ADAMTS), the ubiquitin-proteasome pathway (UPP), tissue plasminogen activator (tPA), and secretases. It is clear that proteases have diverse and important roles in ocular development and disease, and represent, in many cases, useful therapeutic targets for treating ocular conditions, which would otherwise lead to visual impairment.

Animals↗
PubMed2006

Stable and efficient intraocular gene transfer using pseudotyped EIAV lentiviral vectors.

BACKGROUND: We have developed minimal non-primate lentiviral vectors based on the equine infectious anaemia virus (EIAV). We evaluated the in vivo expression profiles of these vectors delivered regionally to ocular tissues to define their potential utility in ocular gene therapy. METHODS: EIAV vectors pseudotyped with VSV-G or rabies-G envelope proteins were delivered subretinally, intravitreally or into the anterior chambers (intracameral administration) in mice. Reporter gene (eGFP) expression was analysed using in vivo retinal imaging or histological examination of eyes and brains at intervals between 3 days and 16 months. We investigated the effects of vector titre, pseudotype, genome configuration, site of intraocular administration, intentional retinal trauma and the degree of retinal maturation on the spatial and temporal expression profiles of these vectors. RESULTS: Subretinal vector delivery resulted in efficient and stable transduction of retinal pigment epithelial (RPE) cells and variable transduction of photoreceptors up to 16 months post-injection. Retinal trauma facilitated the local transduction of neurosensory retinal cells. Intracameral administration of VSV-G- but not rabies-G-pseudotyped vectors produced stable eGFP expression in corneal endothelial cells and trabecular meshwork. CONCLUSIONS: The cellular tropism and expression kinetics of optimised EIAV vectors after intraocular administration make them attractive vehicles for delivering therapeutic genes in the management of inherited and acquired retinal and anterior segment disorders.

Animals↗
PubMed2001

Microscopic anatomy of the eye of the deep-diving Antarctic Weddell seal (Leptonychotes weddellii).

The microscopic anatomy of the eye of the Weddell seal was studied with various light and electron microscopic methods with a view to correlating morphological findings with the biology of this seal which is adapted to the extremes of the Antarctic environment and to extreme diving excursions into the lightless depths of the sea. In the retina an area centralis was found but no fovea centralis. The densely packed photoreceptors consist exclusively of highly differentiated rods, which in primates detect light at low intensity but have rather poor image discrimination. The ganglion cells are relatively scarce, suggesting a high degree of convergence of the light-sensitive cells on the ganglion cells. The pigment epithelium is almost devoid of pigment granules. The extensive tapetum lucidum is about 400-500 microm thick and is composed of about 30 layers of specialized cells. The cornea is 650 (center) to 800-900 (periphery) microm thick. Its structure and glycosaminoglycan histochemistry correspond to that of other mammals. The iridocorneal angle is unusually deep and pervaded by an elaborate trabecular meshwork, which together with a complex canal of Schlemm can be correlated with the ability to absorb large amounts of fluid. The ciliary muscle and its antagonist, the membrane of Bruch, are poorly developed, suggesting relatively poor abilities of accommodation. The combination of a well-developed tapetum lucidum, an unpigmented pigment epithelium, well-developed rods, and a high number of rods converging on only few ganglion cells is obviously an adaptation to an extreme light sensitivity, enabling the animals to make use of the little light available in the deep sea.

Accommodation, Ocular↗
PubMed2001

A large-scale in situ screen provides molecular evidence for the induction of eye anterior segment structures by the developing lens.

The anterior segment of the vertebrate eye includes the cornea, iris, ciliary body, trabecular meshwork, and lens. Although malformations of these structures have been implicated in many human eye diseases, little is known about the molecular mechanisms that control their development. To identify genes involved in anterior segment formation, we developed a large-scale in situ hybridization screen and examined the spatial and temporal expression of over 1000 genes during eye development. This screen identified 62 genes with distinct expression patterns in specific eye structures, including several expressed in novel patterns in the anterior segment. Using these genes as developmental markers, we tested for the presence of inductive signals that control the differentiation of anterior segment tissues. Organ culture recombination experiments showed that a chick lens is capable of inducing the expression of markers of the presumptive iris and ciliary body in the developing mouse neural retina. The inducing activity from the lens acts only over short ranges and is present at multiple stages of eye development. These studies provide molecular evidence that an evolutionarily conserved signal from the lens controls tissue specification in the developing optic cup.

Animals↗
PubMed2000

The lens organizes the anterior segment: specification of neural crest cell differentiation in the avian eye.

During the development of the anterior segment of the eye, neural crest mesenchyme cells migrate between the lens and the corneal epithelium. These cells contribute to the structures lining the anterior chamber: the corneal endothelium and stroma, iris stroma, and trabecular meshwork. In the present study, removal of the lens or replacement of the lens with a cellulose bead led to the formation a disorganized aggregate of mesenchymal cells beneath the corneal epithelium. No recognizable corneal endothelium, corneal stroma, iris stroma, or anterior chamber was found in these eyes. When the lens was replaced immediately after removal, a disorganized mass of mesenchymal cells again formed beneath the corneal epithelium. However, 2 days after surgery, the corneal endothelium and the anterior chamber formed adjacent to the lens. When the lens was removed and replaced such that only a portion of its anterior epithelial cells faced the cornea, mesenchyme cells adjacent to the lens epithelium differentiated into corneal endothelium. Mesenchyme cells adjacent to lens fibers did not form an endothelial layer. The cell adhesion molecule, N-cadherin, is expressed by corneal endothelial cells. When the lens was removed the mesenchyme cells that accumulated beneath the corneal epithelium did not express N-cadherin. Replacement of the lens immediately after removal led to the formation of an endothelial layer that expressed N-cadherin. Implantation of lens epithelia from older embryos showed that the lens epithelium maintained the ability to support the expression of N-cadherin and the formation of the corneal endothelium until E15. This ability was lost by E18. These studies provide evidence that N-cadherin expression and the formation of the corneal endothelium are regulated by signals from the lens. N-cadherin may be important for the mesenchymal-to-epithelial transformation that accompanies the formation of the corneal endothelium.

Animals↗
PubMed2002

The homeobox gene Six3 is a potential regulator of anterior segment formation in the chick eye.

The anterior segment of the vertebrate eye consists of highly organized and specialized ocular tissues critical for normal vision. The periocular mesenchyme, originating from the neural crest, contributes extensively to the anterior segment. During chick eye morphogenesis, the homeobox gene Six3 is expressed in a subset of periocular mesenchymal cells and in differentiating anterior segment tissues. Retrovirus-mediated misexpression of Six3 causes eye anterior segment malformation, including corneal protrusion and opacification, ciliary body and iris hypoplasia, and trabecular meshwork dysgenesis. Histological and molecular marker analyses demonstrate that Six3 misexpression disrupts the integrity of the corneal endothelium and the expression of extracellular matrix components critical for corneal transparency. Six3 misexpression also leads to a reduction of the periocular mesenchymal cell population expressing Lmx1b, Pitx2, and Pax6, transcription factors critical for eye anterior segment morphogenesis. Moreover, elevated levels of Six3 attenuate proliferation of periocular mesenchymal cells in vitro and differentiating anterior segment tissues in vivo. These results suggest that, in addition to its function in eye primordium determination, Six3 plays a role in regulating the development of the vertebrate eye anterior segment.

Animals↗
PubMed1996

Decreased 3 alpha-hydroxysteroid dehydrogenase activity in peripheral blood lymphocytes from patients with primary open angle glaucoma.

The purpose of the present study was to determine whether peripheral blood lymphocytes (PBL) from primary open angle glaucoma (POAG) patients have reduced 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity as was previously found in POAG-derived cultured trabecular meshwork cells. The availability of PBL from both POAG and control patients makes this a useful system for studying the association of decreased 3 alpha-HSD activity with POAG. PBL were isolated from the venous blood of 17 POAG patients and 22 non-glaucoma controls and assayed for 3 alpha-HSD activity with tritiated 5 beta-dihydrocortisol as a substrate. The mean 3 alpha-HSD activity +/- S.E.M., expressed in comparable units of specific activity, of the POAG derived PBL was 13.8 +/- 1.3 U as compared to 32.8 +/- 2.0 U for control cells. This reduction (> 50%) was statistically significant (P < 0.001). Quantitative immunoblot analysis of PBL indicated that the POAG and control cells, despite their difference in 3 alpha-HSD activity, had nearly identical amounts of 3 alpha-HSD protein. The molecular weight of PBL 3 alpha-HSD from both groups of patients was 38,000, the same as previously reported for human liver. The results of this study show an association of decreased PBL 3 alpha-HSD activity and POAG which was not related to antiglaucoma therapy. The reduced levels of 3 alpha-HSD activity in the readily obtainable PBL may serve as a marker for POAG or those at risk for developing the disease.

3-Hydroxysteroid Dehydrogenases↗
PubMed1997

The role of soluble proteins in generating aqueous outflow resistance in the bovine and human eye.

Previous research has shown that wash-out in bovine and primate eyes can be greatly reduced by perfusing with buffer containing 5-15% serum. It was suggested that protein diffusion from the iris root might raise the in vivo protein concentration in the trabecular meshwork to a level much higher than in the anterior chamber. In this study, we investigated the protein concentration in effluent from the outflow pathways in bovine and human eyes, its possible relationship to wash-out, and whether the reduction of wash-out was caused by a bulk protein effect. Bovine and human eyes were placed under silicone oil and perfused with buffer. Outflow facility was continuously determined while effluent was periodically collected from the surface of the eye, and the soluble protein concentration in the effluent was determined. Separate studies were conducted perfusing either albumin or gamma-globulin through bovine eyes. Theoretical models were developed to study the transport of protein into the perfusion fluid. In the bovine eyes, the initial protein concentration in the collected effluent was approximately 1% that of serum, much lower than the 10-15% buffer in serum required to prevent wash-out. Furthermore, the rate of change of outflow facility showed a different dependence on perfused volume than did the protein concentration. Human eyes showed a much higher level of protein in the perfusate, that decayed over a much longer time period. A statistically significant correlation existed between outflow resistance and soluble protein concentration in both bovine and human eyes. However, modelling studies suggested that this correlation might be due to flow resistance setting the flowrate which then determines the protein concentration of the effluent. Separate experiments indicated that the decreased rate of wash-out caused by perfusion of 10-15% serum in buffer was not due to either albumin or gamma-globulin alone. These results suggest that the reduction of wash-out observed in previous studies when serum proteins were perfused through bovine and monkey eyes was not due to the general level of serum proteins but may instead be due to interactions of a particular protein(s).

Animals↗
PubMed1997

Atropine reduces but does not eliminate the age-related decline in perfusion outflow facility in monkeys.

Accommodative amplitude and outflow facility decline with age in rhesus monkeys and humans. In monkeys, there is an age-related reduction in ciliary muscle (CM) mobility due to stiffening of its posterior and outer attachments. Since the CM inserts into the trabecular meshwork (TM) and CM contraction deforms the TM so as to increase outflow facility, we asked whether the age-related decline in outflow facility observed in anesthetized monkeys is consequent to the age-related reduction in CM mobility. One eye of 19 pentobarbital-anesthetized rhesus monkeys aged 4-24 years underwent 2-level constant pressure perfusion of the anterior chamber (AC) for 40 min to measure baseline total outflow facility. Both eyes then received 100 micrograms of atropine, given topically to the central cornea. The AC of the second eye was cannulated 40 min after atropine treatment. Facility was measured simultaneously in both eyes for 40 min beginning 45 min after atropine treatment. Baseline facility declined with age by -0.0160 +/- 0.0059 microliters min-1 mmHg-1 yr-1 (P = 0.009). The average facility at baseline was approximately 50% higher in the youngest (ages 4-10 years) compared to the oldest (ages 21-25 years) animals (P < or = 0.03). Following atropine facility decreased by approximately 25% in the youngest monkeys (N.S.), but not at all in the oldest animals when compared to baseline. Thus, the age-related facility decline persisted after atropine in both eyes, but was not as dramatic as prior to atropine (-0.0092 +/- 0.0050 [P < or = 0.09] and -0.0078 +/- 0.0044 [P < or = 0.10] microliter min-1 mmHg-1 yr-1 respectively). Apparently, atropine inhibits facility-relevant anesthetic-induced ciliary muscle tone to a greater extent in younger than in older monkeys, presumably because stiffening of the posterior and outer attachments of the CM in the older animals has already reduced its ability to move and thereby deform the TM. The inability of atropine to completely eliminate the age-related facility decline indicates the presence of atropine-independent, facility-relevant age-dependent changes in the TM itself, such as loss of cells or build-up of extracellular material.

Aging↗
PubMed1997

Intraocular pressure and outflow facility are unchanged following acute and chronic intracameral chondroitinase ABC and hyaluronidase in monkeys.

We determined the effect of chronic and acute loss of glycosaminoglycans from the aqueous outflow pathway on intraocular pressure (IOP) and outflow facility in the subhuman primate eye. For the study of the chronic effects of the GAGases, cynomolgus monkeys received intracameral injections of hyaluronidase (Streptomyces, 5 or 50 units, n=2) or chondroitinase ABC (0.05 or 0.25 units, n=2) biweekly for 8 months (4 months for each dose). IOP was measured at 3, 7, 10 and 14 days after each injection. Outflow facility (2-level constant pressure) was determined at 2, 4, 6, and 8 months. Monkeys were killed 6 days after the last injection. The changes in the distribution of hyaluronic acid and sulfated proteoglycans in the outflow pathway were examined using substrate-specific histochemical techniques. The acute effects of these enzymes on outflow facilities (30 min or 2 hr after enzyme) were determined in another group of animals (n=4 for each time enzyme-1). IOP and outflow facility were unchanged compared to controls (heat inactivated enzyme) at any time in the chronically or acutely treated monkeys. Hyaluronic acid staining was absent in the outflow pathways of eyes treated chronically with hyaluronidase compared with control eyes, while collagen-associated sulfated proteoglycans were decreased but not completely removed by the chronic chondroitinase ABC treatment. Chronic loss of these glycosaminoglycans from the trabecular meshwork does not appear to contribute to the IOP elevation and decrease in outflow facility that accompanies open-angle glaucoma. Most importantly, no increase in outflow facility was found with acute hyaluronidase or chondroitinase treatment.

Animals↗
PubMed1998

Regulation of endothelin-1 in human non-pigmented ciliary epithelial cells by tumor necrosis factor-alpha.

Endothelins (ET) are potent vasoactive peptides present in many ocular structures and are formed from precursor Big endothelins (Big ET-1) by the action of an endothelin-converting enzyme (ECE). ET-1 is thought to decrease intraocular pressure by contracting the ciliary muscle thus enhancing the outflow of aqueous humor through the Canal of Schlemm and trabecular meshwork. However, the mechanisms involved in the regulation of endothelin-1 (ET-1) synthesis and release in ocular tissues have not been fully characterized. In this study we examined the effect of tumor necrosis factor-alpha(TNF-alpha; 10 nm), a proinflammatory cytokine, on the cellular mechanisms leading to ET-1 synthesis and release in SV-40 transformed human ciliary non-pigmented epithelial cells (HNPE). ET-1 and Big endothelin-1 (Big ET-1) immunoreactivity was time-dependently increased following TNF-alphatreatment. Phorbol esters (PMA), activators of PKC, also raised the immunoreactive levels of ET-1 and Big ET-1 while, staurosporine, a PKC inhibitor (20 nm), decreased ET-1 levels in TNF-alpha-stimulated cells. Pre-treatment with phosphoramidon (1 micron) an ECE-inhibitor, followed by TNF-alpha stimulation, decreased ir-ET-1 levels. Cycloheximide (9 micron), a protein synthesis inhibitor, decreased TNF-alpha-stimulated levels for ir-ET-1 and ir-Big ET-1, suggesting that TNF-alpha may be directly regulating ET-1 expression at the ET-1 gene. Our data indicates that TNF-alpha regulates ET-1 levels in HNPE cells possibly by activating PKC either to stimulate protein synthesis and/or to enhance ET-1 secretion. These results suggest that ET-1 released from the ciliary body may play an important role in aqueous humor dynamics following cytokine activation.

Cells, Cultured↗
PubMed1998

Glutamine immunoreactivity in Müller cells of monkey eyes with experimental glaucoma.

The action of glutamate in retina is largely terminated through rapid uptake by Müller cells and subsequent conversion primarily to glutamine. Glutamine, transferred from Müller cells to neurons, serves as a precursor for the formation of glutamate in neurons completing the glutamate-glutamine cycle. In a monkey model of high-tension glaucoma, we have examined glutamine immunoreactivity in the Müller cell as well as the number of Müller cells to determine whether the activity of these cells in the glutamate-glutamine cycle is affected, particularly since high vitreal glutamate has been reported in glaucoma. Unilateral glaucoma was induced in three monkeys by argon laser application to the trabecular meshwork. LR White sections of retina from the temporal mid-periphery (about 23 degrees) and the parafovea (central 3 degrees) were immunolabeled for glutamine using immunogold and silver intensification. The percentage difference in labeling intensity (darkness) in the glaucomatous retina was determined relative to the labeling found in the control retina by image analysis. Ganglion cell density was estimated from radial sections in the parafovea and from retinal whole mounts in the mid-periphery. The number of Müller cells was estimated from vibratome sections immunolabeled by vimentin antibodies in the temporal mid-periphery (about 30 degrees). Glutamine immunoreactivity was localized predominately in ganglion cells and Müller cells. However, the intensity of glutamine immunolabeling was greater in Müller cells of glaucomatous eyes than in control eyes. This increase in glutamine immunolabeling was 25-32% in the temporal mid-periphery and 27-48% in the parafovea. Müller cell number in the glaucomatous eye was similar to that of the control in the temporal mid-periphery. The data in this study indicate that the increase in glutamine in Müller cells is not a consequence of their loss and that Müller cell function in the glutamate-glutamine cycle continues in glaucomatous eyes. These findings are consistent with a previous report that extracellular/vitreal glutamate concentration is elevated in high-tension glaucoma.

Animals↗
PubMed1999

Combined effects of H-7 and cytochalasin B on outflow facility in monkeys.

The serine-threonine protein kinase inhibitor H-7 and the fungal metabolite cytochalasin B (CB) disrupt the actin microfilament network by different mechanisms, and increase outflow facility similarly in live monkeys. Their combined effect has therefore determined on total outflow facility in cynomolgus monkeys by 2-level constant pressure perfusion. (1) After unilateral anterior chamber (AC) bolus injection of H-7 [10 micrometers, 100 micrometers (subthreshold for increasing facility when given alone) or 500 micrometers (just-threshold)] followed by bilateral AC bolus injection of CB [2 micrograms (strong but submaximal for increasing facility when given alone)], no significant difference between eyes was observed. (2) After bilateral AC exchange with a subthreshold dose of H-7 (10 micrometers) followed by unilateral AC bolus injection of a subthreshold dose of CB (0.02, 0.05, 0.1 or 0.5 microgram), 10 micrometers H-7 plus 0.1 or 0.5 microgram CB increased facility by approximately 40 or 80% compared to 10 micrometers H-7 alone. (3) After bilateral AC exchange with a maximal dose of H-7 (300 micrometers), followed by unilateral AC bolus injection of a subthreshold dose of CB (0.1 or 0.5 microgram), 300 micrometers H-7 plus 0.5 microgram CB increased outflow facility by 47% compared to 300 micrometers H-7 alone. (4) After unilateral AC exchange with a maximal dose of H-7 (300 micrometers) followed by bilateral AC bolus injection of a near-maximal dose of CB (2 micrograms), 300 micrometers H-7 plus 2 micrograms CB increased the facility by 67% compared to 2 micrograms CB alone. The significant effect of combined subthreshold doses of H-7 and CB on outflow facility, the potentiation of the facility-increasing effect of a maximal H-7 dose by both subthreshold and near-maximal CB doses, and the known cytoskeletal effects of both compounds, may suggest that both increase facility by disrupting actin filaments in the trabecular meshwork.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1999

Stimulus-specific and cell type-specific cascades: emerging principles relating to control of apoptosis in the eye.

Apoptosis has a critical role in development, homeostasis, wound healing, and the pathophysiology of disease in the organs of multicellular organisms. It has been implicated in these processes in retina, lens, cornea, trabecular meshwork, optic nerve, and the central nervous system pathways that contribute to vision. Considerable interest has been focused on inhibiting apoptosis to control disease and wound healing processes in which programmed cell death is thought to have a critical role. A simplified view led to the search for effective inhibitors of 'the final common pathway for apoptosis'. Recent studies have provided important insights into the modulators that participate in and regulate the apoptosis cascades which are activated in response to cytokines, ionizing radiation, chemotherapeutic agents, growth factor deprivation, and other stimulators of cell death. These studies lead to the inescapable conclusion that the apoptosis pathways are not only stimulus-specific, but also cell-type specific. These observations have important implications related to development of pharmacological strategies for controlling apoptosis-associated disease and apoptosis-initiated wound healing.

Apoptosis↗
PubMed2001

Expression of myocilin/TIGR in normal and glaucomatous primate optic nerves.

Myocilin/TIGR was the first molecule discovered to be linked with primary open angle glaucoma (POAG), a blinding disease characterized by progressive loss of retinal ganglion cells. Mutations in myocilin/TIGR have been associated with age of disease onset and severity. The function of myocilin/TIGR and its role in glaucoma is unknown. Myocilin/TIGR has been studied in the trabecular meshwork to determine a role in regulation of intraocular pressure. The site of damage to the axons of the retinal ganglion cells is the optic nerve head (ONH). The myocilin/TIGR expression was examined in fetal through adult human optic nerve as well as in POAG. Myocilin/TIGR was expressed in the myelinated optic nerve of children and normal adults but not in the fetal optic nerve before myelination. Also examined was the expression in monkeys with experimental glaucoma. The results demonstrate that optic nerve head astrocytes constitutively express myocilin/TIGR in vivo in primates. Nevertheless, myocilin/TIGR is apparently reduced in glaucomatous ONH. The colocalization of myocilin/TIGR to the myelin suggests a role of myocilin/TIGR in the myelinated optic nerve.

Adolescent↗
PubMed1998

Glutamate receptor subunit GluR2 and NMDAR1 immunoreactivity in the retina of macaque monkeys with experimental glaucoma does not identify vulnerable neurons.

Excitatory amino acid neurotoxicity has been proposed as a mechanism underlying selective neuronal death in glaucoma. The relationships between the cellular distribution of glutamate receptor subunit proteins GluR2 and NMDAR1 and the vulnerability of restricted retinal neuron subpopulations was explored in experimental glaucoma in macaque monkeys, produced by treating the trabecular meshwork in one eye with argon or diode laser burns. Immunostaining of retinal segments was performed using specific monoclonal antibodies to the GluR2 and NMDAR1 subunit proteins as well as neurofilament protein. The distribution of immunoreactivity was qualitatively assessed in the retina, and ganglion cells were counted in the paracentral and peripheral regions of each retinal segment. Immunoreactivity for both of these glutamate receptor subunit proteins was widely distributed in most retinal neuron types in control eyes and was colocalized with neurofilament protein in ganglion cells. In the glaucomatous eyes, densities of GluR2- and NMDAR1-immunoreactive ganglion cells were dramatically reduced compared to unaffected fellow eyes, but GluR2- and NMDAR1-immunoreactive populations of horizontal, bipolar, and amacrine cells were not affected. These data parallel previous observations on the selective vulnerability of ganglion cells in this experimental model of glaucoma. However, GluR2 and NMDAR1 subunits do not constitute cell type-specific markers of vulnerability in glaucoma as they are present in neurons prone to degeneration as well as in resistant ones. While retinal pathology in glaucoma involves excitotoxic mechanisms that may be related to glutamate receptor subunits regulating calcium fluxes, the specific pattern of neuronal vulnerability clearly depends on other cellular characteristics such as morphology, connectivity, and other aspects of the neurochemical phenotype.

Animals↗