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PubMed2001

Experimental glaucoma in primates: changes in cytochrome oxidase blobs in V1 cortex.

PURPOSE: To evaluate the effects of ganglion cell depletion from experimental glaucoma on the relative metabolic activities of neurons in the cytochrome oxidase blobs of V1 cortex in the macaque visual system. METHODS: Monocular experimental glaucoma was induced in adult monkeys (Macaca mulatta and Macaca fascicularis) by laser application to the trabecular meshwork, increasing the intraocular pressure. After other experiments, the primary visual cortices were analyzed for functional excitation from surviving ganglion cells, as indicated by cytochrome oxidase histochemistry. RESULTS: Cytochrome oxidase reactivity was uniformly reduced in blobs with input from the glaucomatous eye in a manner consistent with loss of known afferent inputs. The average size of glaucomatous blobs in layers 2 and 3 of V1 cortex was reduced by half. CONCLUSIONS: Experimental glaucoma in monkeys reduces retinal input to the central nervous system, thereby reducing the metabolic drive to downstream targets, as indicated by the reduction in the size of cytochrome oxidase blobs in layers 2 and 3 of V1 cortex. The pattern of cytochrome oxidase loss within the blob was uniform, suggesting that all sources of afferent input to the blobs were affected by experimental glaucoma.

Afferent Pathways↗

PubMed2003

Characterization of rabbit myocilin: Implications for human myocilin glycosylation and signal peptide usage.

BACKGROUND: Mutations in the gene encoding human myocilin (MYOC) have been shown to cause juvenile- and adult-onset glaucoma. In addition, myocilin has been associated with glucocorticoid-induced ocular hypertension and steroid-induced glaucoma. To better understand the role myocilin plays in steroid-induced glaucoma and open-angle glaucoma, we examined rabbit myocilin for use in the rabbit animal model of steroid-induced glaucoma. RESULTS: We have cloned the rabbit ortholog of human MYOC. Rabbit MYOC consists of three exons and an open reading frame encoding a 490 amino acid, 54,882-Da protein, which is 14 amino acids shorter at the N-terminus than human myocilin but 84% identical overall. Rabbit myocilin migrates as a single electrophoretic band, vs. double-banded human myocilin, by SDS-PAGE/immunoblot analysis. We determined that the differential migration exhibited is due to an N-glycosylation site that is present in human (Asn57), monkey and mouse myocilin but absent in rabbit (Ser43), rat and bovine myocilin. Rabbit myocilin is secreted in vitro in trabecular meshwork cell culture and in vivo in aqueous humor. Secretion of human myocilin is shown to be dependent on the signal peptide and independent of the extra 14 amino acids not found in rabbit myocilin. Many of the amino acids in myocilin that are mutated in glaucoma patients are conserved across species. CONCLUSION: We have cloned the rabbit MYOC cDNA and determined that rabbit myocilin is secreted but not N-linked glycosylated. Knowledge of the rabbit MYOC cDNA sequence will facilitate future studies in the rabbit animal model examining the role of myocilin in steroid-induced glaucoma and the gain-of-function hypothesis in open-angle glaucoma.

Amino Acid Sequence↗

PubMed1998

[An experimental study of human trabecular cell growth on a filter and hydraulic conductivity].

OBJECTIVE: To search a method of culturing human trabecular meshwork cells (HTC) on a filter support and provide a model to study the hydraulic conductivity of HTC in vitro. METHODS: The 3rd passage of HTC was cultured on a nylon filter, after that we measured the rate of different irrigation through the filter with HTC [Lp, microl/(min x mmHg x cm(2))]. RESULTS: HTC could continuously grow on the filter. The normal Lp was 10.45 microl/(min x mmHg x cm(2)). When the model was irrigated respectively by the solution containing epinephrine (EPI) and dexamethasone (DEX), the Lp value of HTC cultured in the same period was significantly higher than that of the normal group. However, after HTC exposed to DEX for a few days, Lp was significantly decreased. CONCLUSIONS: (1) Better information of hydraulic conductivity and the effects of medicine on HTC can be obtained from the dynamic filter model; (2) EPI can improve the conductivity of HTC, and DEX can do the same in early period.

Animals↗

PubMed2004

[Deep sclerectomy using a hyaluronate implant versus trabeculectomy. A comparison of two glaucoma operations using mitomycin C].

BACKGROUND: It was investigated whether a very low target pressure could be achieved by modification of deep sclerectomy without losing the advantages of non penetrating surgery in comparison to conventional filtration surgery. PATIENTS AND METHODS: A total of 22 eyes from 22 patients with advanced open angle glaucoma were randomly assigned to receive a deep sclerectomy or a trabeculectomy. Both groups received 0.02% mitomycin C under the conjunctiva prior to preparation of the scleral flap. In the deep sclerectomy group at least parts of the outer trabecular meshwork were removed until an apparent filtration was achieved. A dry cross-linked hyaluronate served as an implant. In the other group a classical trabeculectomy was performed. RESULTS: The median intraocular pressure 12 months post-operation was 11.5 mm Hg in the deep sclerectomy group compared to 11 mm Hg in the trabeculectomy group; the median of the relative IOP reduction was -47% in the deep sclerectomy group, and -57% in the trabeculectomy group. The best corrected visual acuity was unchanged 12 months postoperatively in both groups. DISCUSSION: As a more aggressive IOP-lowering procedure (intended filtration, use of antimetabolites) deep sclerectomy proved to be as effective as trabeculectomy. Nevertheless, the advantages of the more difficult surgical procedure concerning visual acuity, complications and surgical interventions were lost postoperatively.

Adult↗

PubMed2002

[The role of myocilin in the pathogenesis of primary open-angle glaucoma].

Mutations in myocilin are responsible for autosomal-dominant inherited juvenile open-angle glaucoma and some subgroups of adult-onset glaucoma (POAG). Myocilin is a secreted glycoprotein with a molecular weight of approximately 55-57 kDa that forms dimers and multimers. Structural motives are domains that have similarities with myosin and olfactomedin, a signalling sequence as well as a leucine zipper at the N-terminus of myocilin. Most mutations that were identified in patients with POAG are localized in the olfactomedin domain which is highly conserved between species. In the eye, myocilin is highly expressed in the trabecular meshwork (TM), the sclera, the ciliary body and the iris, lower amounts are seen in the retina and the optic nerve. In addition, secreted myocilin is detected in the aqueous humor. In the chamber angle, myocilin is associated with fibrillar components of the extracellular matrix in the cribriform portion of the TM. Myocilin binds specifically to the HepII domain of fibronectin. In organ cultures of perfused anterior eye segments, recombinant myocilin increases outflow resistance. In cultured TM cells, myocilin is induced by treatment with dexamethasone in a similar time course as observed in steroid-induced glaucoma. Myocilin is also induced by transforming growth factor-beta (TGF-beta) and mechanical stress. Mice with a targeted disruption of the myocilin gene do not express a phenotype. Experimental data indicate that mutated myocilin is not secreted and accumulates in cells which might critically impair the function of the TM.

Animals↗

PubMed2002

A myosin light chain kinase inhibitor, ML-9, lowers the intraocular pressure in rabbit eyes.

The role of myosin light chain kinase (MLCK) in regulating the intraocular pressure (IOP) and outflow facility in rabbit eyes were studied. The IOP and pupil diameter were determined before and after intracameral and intravitreal administration of ML-9, a specific MLCK inhibitor. Total outflow facility and uveoscleral outflow facility was determined 3hr after intracameral administration of ML-9. Immunoblotting was performed to identify MLCK and the 20-kDa light chain of myosin (MLC) isoforms in human trabecular meshwork (TM) cells. The phosphorylation status of MLC was examined following ML-9 treatment. The effects of ML-9 on the morphology and actin and vinculin distribution in cultured TM cells were also studied. In rabbit eyes, administration of ML-9 resulted in a dose-dependent decrease in IOP. An increase of the outflow facility was also observed. Immunoblot analysis revealed the presence of MLCK in human TM cells. Exposure to ML-9 dose-dependently inhibited MLC phosphorylation/activation. The inhibitor caused retraction and dissociation of cells, disruption of actin bundles and impairment of focal adhesion formation in TM cells. ML-9 induces a reduction in IOP and an increase in the outflow facility in rabbit eyes. The IOP-lowering effects may be related to alterations in TM cell shapes. Inhibitors of MLCK may potentially be developed into novel medications for glaucoma.

Actins↗

PubMedDate not supplied

Primary infantile glaucoma (congenital glaucoma).

Primary infantile glaucoma, commonly termed congenital glaucoma or trabeculodysgenesis, is an unusual, inherited connatal anomaly of the trabecular meshwork and anterior chamber angle which leads to obstruction of aqueous outflow, increased intraocular pressure, and optic nerve damage. Its pathogenesis is still disputed; most observers have not been able to document ultrastructurally a continuous endothelial membrane, as initially advanced by Barkan. Medical therapy for primary infantile glaucoma is accorded a supportive role; the primary, definitive treatment is surgical. Both goniotomy and trabeculotomy ab externo give similarly good results in the majority of patients. The prognosis in this disease is related to the time of its initial presentation, initial surgical intervention, degree of optic nerve damage, nature and quality of corneal enlargement and astigmatism, progressive refractive error, and anisometropic amblyopia. The inability to easily quantitate visual acuity and extent of visual loss in neonates makes these parameters less helpful in following patients than measurement of corneal diameter and intraocular pressure. However, even these data should not be relied upon exclusively to determine the quality or quantity of success in primary infantile glaucoma.

Anterior Chamber↗

PubMed1992

Ethacrynic acid induces reversible shape and cytoskeletal changes in cultured cells.

Cell cultures derived from trabecular meshworks of human and bovine eyes and from bovine vascular endothelia were incubated at 37 degrees C for 1 hr with ethacrynic acid (ECA, 0.1-0.5 mmol/l) dissolved in culture medium. At 2 hr after the initial exposure, ECA at concentrations up to 0.4 mmol/l induced a reversible alteration in cell shape in all three cell types that was coincident with a change in the staining pattern of major cytoskeletal components including actin, alpha-actinin, vinculin, and vimentin. Distinct progressive alterations in beta-tubulin also occurred, with initial changes observed 10 min after ECA exposure. The ECA-induced changes in tubulin were blocked in part by preincubation with taxol (which stabilizes the microtubule structure), but they appeared to differ from those occurring with nocodazole (which interferes with tubulin assembly). These results suggest the possibility that ECA-induced increases in outflow facility may be mediated by alterations in the cytoskeletons of outflow pathway cells.

Adolescent↗

PubMed1986

Delayed response to argon laser trabeculoplasty in monkeys. Morphological and morphometric analysis.

In eight cynomolgus monkeys we performed argon laser trabeculoplasty and evaluated morphological changes in the trabecular meshwork (TM). Four weeks after laser treatment, the treated spots were detected as regions of flattened and collapsed beams covered by a cellular sheet extending from the corneal endothelium. The inner wall of Schlemm's canal beneath these regions was flat, with no vacuoles despite fixation with intraocular pressure maintained at 15 mm Hg. Adjacent nonlasered spots had wide open intertrabecular spaces with herniations of juxtacanalicular TM and of inner wall endothelium into and across the lumen of Schlemm's canal. The herniations contained chronic inflammatory cells and large vacuoles. Statistical morphometric analysis in three monkeys established that these herniations were significantly wider, more numerous, and contained more vacuoles than did control eyes. Our findings suggest that a biologic process is involved in these reactions to argon laser trabeculoplasty. Scarring is seen to obliterate TM in spots treated by the laser, and this apparently causes the flow of the aqueous humor to be diverted through adjacent nonlasered regions that become structurally altered to compensate for this overload of flow.

Animals↗

PubMed1981

Trabeculectomy.

In a critical review of trabeculectomy, some factors and steps that I consider important for its successful outcome are discussed. Trabeculectomy is a misnomer, because the success of this procedure does not depend on inclusion of trabecular meshwork or Schlemm's canal in the excised tissue. Furthermore, development of a conjunctival bleb is seen in most, if not all, eyes with successful trabeculectomy. Trabeculectomy is, then, a form of guarded filtering procedure. Several factors seem to determine the outcome of the final intraocular pressure control after trabeculectomy. In this study, intracameral air injection and gauging of the closure of the lamellar scleral flap according to an air test during trabeculectomy proved very useful in attaining optimal closure of the lamellar scleral flap. It was effective in preventing undesirable postoperative complications as well as in achieving a satisfactory success rate. Trabeculectomy, as reported by others, seems to be a remarkably successful and safe procedure. However, the results in aphakic glaucoma are disappointing. From all indications at the present time, trabeculectomy will stay with us as a primary procedure for open-angle and chronic angle-closure glaucomas in adult phakic eyes, although we do not yet know how many of the eyes with seemingly successful trabeculectomies will remain healthy in the future.

Adult↗

PubMed1984

Nonsteroidal anti-inflammatory agents after argon laser trabeculoplasty. A trial with flurbiprofen and indomethacin.

Seventy glaucomatous eyes received argon laser trabeculoplasty (ALT) to 180 degrees of the trabecular meshwork. Thirty-six eyes were treated with topical .03% sodium flurbiprofen, a nonsteroidal anti-inflammatory agent; 34 eyes received placebo. Eighteen eyes received ALT to 360 degrees of the meshwork; nine of these eyes were treated with topical 1% indomethacin and nine eyes received placebo. Eyes treated with flurbiprofen and indomethacin showed significantly less conjunctival injection following ALT. However, these agents did not significantly alter the anterior chamber reaction after laser therapy compared to placebo. Flurbiprofen-treated eyes showed a significantly smaller percent (32.6%) decrease in intraocular pressure (IOP) one day after ALT as compared to eyes receiving placebo (43.8%). In addition, a higher percentage of placebo treated eyes had a fall in IOP of at least 10 mmHg up to five weeks after ALT. Within the indomethacin protocol, the percentage change in IOP was comparable for both indomethacin and placebo treated eyes. Mild ocular symptoms (itching, burning, foreign-body sensation) developed in 77.8% of flurbiprofen-treated eyes, in 55.6% of indomethacin-treated eyes, and in 20.9% of eyes receiving placebo.

Adult↗

PubMed1991

Outflow facility studies in the perfused human ocular anterior segment.

We have recently developed a tissue model of the human aqueous outflow pathway involving placement of the eviscerated anterior corneoscleral shell, [with lens and uveal tissue removed but trabecular meshwork (TM) attached] onto a specialized perfusion apparatus. The TM and associated outflow tissues are perfused with culture medium at a physiologically-relevant perfusion pressure in a 5% CO2 environment at 37 degrees C. Under these conditions, the perfused outflow tissues are similar for several days, to the human and/or subhuman primate outflow system in vivo with regard to morphology as well as several functional parameters. Measured facility of outflow (0.271 +/- 0.018 microliters min-1 mmHg-1, n = 79) is similar to facility values obtained by tonography in living human beings. Moreover, outflow facility decreases in a linear fashion with increased perfusion pressure by 1.4% mmHg-1. Finally the removal of the TM results in a 41% decrease in measured outflow resistance. The ability to study viable human outflow tissue for at least several days and the opportunity to establish a model which serves as an alternative to animal testing, point to the potential importance of this technique in investigating the biology of the aqueous outflow system.

Anterior Eye Segment↗

PubMed1986

Laser-induced glaucoma in rabbits.

Argon laser energy was applied to the trabecular meshwork of pigmented rabbits in an attempt to develop an animal model of 'glaucoma'. Laser energy was varied to determine the optimal level needed to produce sustained ocular hypertension. An initial response of ocular hypertension followed by hypotension was observed in all of the animals tested. Approximately half of the laser-treated rabbits developed a secondary buphthalmus and sustained ocular hypertension. In these animals outflow facility was decreased by approximately 60%. Histologic examination at 4- and 8 weeks after laser treatment demonstrated a wound-healing response resulting in closure of the intertrabecular spaces and obstruction of outflow to injected carbon particles. Optic nerve cupping and a loss of ganglion cells were also observed. Topical application of L-timolol (0.5%), pilocarpine (2.0%) and forskolin (1.0%) were found to be effective in decreasing intraocular pressure in the laser-treated, hypertensive eye with no significant effect in control non-laser-treated eyes, suggesting that this model can be a useful tool for screening potential antiglaucoma medications.

Animals↗

PubMed1997

Increased extracellular deposition of fibrillin-containing fibrils in pseudoexfoliation syndrome.

PURPOSE: To localize the distribution of fibrillin-containing microfibrils in normal human anterior segment tissues and to characterize the role of fibrillin in the pathogenesis of pseudoexfoliation syndrome. METHODS: Anterior segment tissues were obtained from 10 eyes with pseudoexfoliation syndrome and 10 normal eyes and investigated by indirect immunofluorescence and electron microscopic immunogold labeling using a monoclonal antibody to fibrillin-1. RESULTS: In addition to labeling of zonular fibers, fibrillin-immunoreactive microfibrillar bundles generally were found in the corneal stroma; the stromal connective tissues of conjunctiva, ciliary body, and iris, especially in the iris root area; the periphery of Schlemm's canal, the scleral spur, and the most anterior portion of the trabecular meshwork; the ciliary muscle, and the dilator and sphincter muscles of the iris; the basement membranes of peripheral corneal epithelium, conjunctival epithelium, ciliary pigmented epithelium, and the lens capsule. The microfibrillar bundles were found to be isolated or in association with elastic fibers and cellular basement membranes. In pseudoexfoliation eyes, an additional strong immunoreaction was localized to pseudoexfoliation fibers and their microfibrillar subunits in close proximity to surfaces of cells involved in pseudoexfoliation fiber production. CONCLUSIONS: The fibrillin-containing microfibrillar system in normal ocular tissues is suggested to have a substantial role in the maintenance of tissue integrity by providing tensile strength and flexibility to mechanically strained tissues. The findings further provide evidence for fibrillin as an intrinsic component of pseudoexfoliation fibers, suggesting the possibility that enhanced expression of fibrillin or abnormal aggregation of fibrillin-containing microfibrils may be involved in the pathogenesis of pseudoexfoliation syndrome.

Aged↗

PubMed2006

Numerical solution of ocular fluid dynamics in a rabbit eye: parametric effects.

Numerical calculations of the aqueous humor dynamics in the anterior chamber of a rabbit's eye are presented to delineate the basic flow mechanisms. The calculations are based on a geometrical model of the eye, which represents the Trabecular meshwork (TM) as a multilayered porous zone of specified pore sizes and void fraction. The outer surface of the cornea is assumed to be at a fixed temperature (corresponding to the ambient temperature), while the iris surface is assumed to be at the core body temperature. Results are obtained for both the horizontal upward-facing orientation of the eye, and the vertical orientation of the eye. Parameters varied include: the temperature difference between the iris and the cornea to underscore the important role of buoyancy in driving the aqueous humor flow; and, the pupil size reflecting different levels of ambient light. Buoyancy is observed to be the dominant driving mechanism for the convective motion in both orientations of the eye. Variations in the pupil size appear to have little influence on the IOP or flow distribution in view of the dominant role of buoyancy in controlling the flow motion. The study provides distributions of the shear stress and flow patterns and delineates the important role of the eye-orientation on these results.

Animals↗

PubMed2006

Corneal toxicity of cell-penetrating peptides that inhibit Herpes simplex virus entry.

Cell-penetrating peptides (CPPs) inhibit Herpes simplex virus entry at low micromolar concentrations and may be useful either as prophylactic or therapeutic agents for herpetic keratitis. The aim of this study was to assess the in vitro and in vivo toxicity of three CPPs-EB, TAT-C, and HOM (penetratin)-for the cornea. Incubation of primary (HK320) or immortalized (THK320) human keratocytes with the EB peptide (up to 100 microM), bHOMd (up to 200 microM), or TAT-C (up to 400 microM) resulted in no evidence of toxicity using a formazan dye-reduction assay. Similar results were obtained with a human trabecular meshwork cell line (TM-1), primary human foreskin fibroblasts (DP-9), Vero, and HeLa cells with EB and TATC. The bHOMd peptide showed some toxicity in Vero and HeLa cells, with CC50 values of 70 and 93 microM, respectively. The EB peptide did not inhibit macromolecular synthesis in Vero cells at concentrations below 150 microM, although cell proliferation was blocked at concentrations of EB above 50 microM. In vivo toxicity was assessed by applying peptides in Dulbecco's modified Eagle's medium to the cornea 4 times daily for 7 d. At concentrations 1000 times the IC50 values, the EB and bHOM peptides showed no toxicity, whereas TAT-C caused some mild eyelid swelling. Some slight epithelial cell sloughing was seen with the bKLA peptide in vivo. These results suggest that these CPPs-and EB in particular-have a favorable toxicity profile, and that further development is warranted.

Animals↗

PubMed2005

Overexpression and properties of wild-type and Tyr437His mutated myocilin in the eyes of transgenic mice.

PURPOSE: To obtain experimental in vivo information on the functional properties of myocilin for aqueous humor (AH) outflow and to study in vivo the processing of mutated Tyr437His myocilin. Myocilin is a secreted glycoprotein that is mutated in some forms of primary open-angle glaucoma (POAG), and patients with the Tyr437His mutation have severe phenotypes. METHODS: The chicken betaB1-crystallin promoter was used to overexpress wild-type human myocilin and mutated Tyr437His myocilin in the lenses of transgenic mice. Expression of transgenic mRNA was monitored by Northern blot analysis and in situ hybridization. The localization and secretion of transgenic myocilin was investigated by Western blot analysis and light and electron microscopy. Intraocular pressure (IOP) was measured by anterior chamber cannulation. RESULTS: Two independent lines were established with each of the constructs that showed a strong expression of transgenic mRNA in their lenses. Transgenic expression resulted in a 4.7 +/- 1.8-fold increase of secreted normal myocilin in mouse AH, compared with its concentration in human AH. Immunoreactivity for transgenic myocilin was observed along the surfaces of lens and corneal endothelium, and in the chamber angle. At 12 weeks of age, the ultrastructure of the trabecular meshwork in mice expressing normal myocilin was not different from that of control eyes, and IOP of transgenic animals did not significantly differ from that of control littermates. In contrast, mutated Tyr437His myocilin was not secreted from lens fibers, but accumulated in dilated cisterns of rough endoplasmic reticulum. Although no structural changes were observed in lenses of animals expressing normal myocilin, lenses with Tyr437His expression developed nuclear cataracts, completely lost transparency, and eventually ruptured. Structural changes in lenses of Tyr437His expressing mice were correlated with a significant increase in IOP. CONCLUSIONS: The results do not support the concept that increasing amounts of myocilin in the outflow tissues obstruct the system and directly cause an increase in outflow resistance. Mutated Tyr437His myocilin is not secreted in vivo and causes severe alterations of cellular structure and function. A comparable mechanism may cause POAG in patients with myocilin mutations.

Animals↗

PubMed2006

The effect of temperature on gene silencing by siRNAs: implications for silencing in the anterior chamber of the eye.

Gene silencing by siRNAs offers the potential for reducing the expression of mutated genes that cause disease. It has been shown that the folding or secondary structure of a specific mRNA was significantly correlated to the silencing observed. Since this base pairing is dependent on free energy, the temperature of the cells may influence the effectiveness of a particular siRNA. The aqueous humor of the human eye has been measured to be around 34 degrees C with the lens acting as a thermal barrier in the eye. The trabecular meshwork, bathed by the aqueous humor, probably has a temperature lower than body temperature under normal conditions. Mutated myocilin, that is associated with primary open angle glaucoma, would appear to be a candidate for silencing by siRNAs. Silencing of the mutated myocilin might prevent additional accumulation of this protein in the rough endoplasmic reticulum. These experiments were undertaken to determine the influence of lowered temperatures on the silencing of myocilin by five siRNAs. Three different patterns of silencing emerged when the silencings were compared with cells grown at 33, 35, and 37 degrees C. For one of the siRNAs, the silencing was increased at lower temperatures. For two siRNAs, no significant changes in silencing were observed with different temperatures. Two of the siRNAs were significantly influenced by temperature with little if any silencing occurring at the lowest temperature. These data indicate that siRNAs directed to tissues in the anterior chamber of the eye should be checked at temperatures lower than 37 degrees C to determine their effectiveness.

Anterior Chamber↗