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| April 2002 | Inside IOVS | Volume 43/4 |
| Drugs and Natural Agents: Preserving Ocular Health |
Nilvadipine and Retinal Degeneration
RCS rat is the most extensively studied animal model for understanding the molecular pathology retinitis pigmentosa (RP). To evaluate drug effects of several kinds of Ca2+ antagonist on the retinal degeneration of RCS rats, several kinds of Ca2+ antagonists, D-cis-diltiazem, nicardipine, nilvadipine or nifedipine, were intraperitoneal administrated and thereafter retinal morphology and functions were analyzed. Yamazaki et al. (p. 919) found that systemic administration of only nilvadipine among these Ca2+ antagonists caused preservation of retinal morphology and functions of electroretinogram responses in RCS rats during the initial stage of the retinal degeneration.
Integrin, MMP, and Corneal Neovascularization
Neovascularization occurs through at least two separate pathways based on the selective expression of either the avb3 or avb5 integrins. Thus, the successful application of therapeutic strategies as well as targeting of neovascularization through adhesion receptors is dependent on the integrin subfamilies expressed. In the corneal alkaline burn model of neovascularization, Zhang et al. (p. 955) have demonstrated that the avb5 integrin is selectively expressed on endothelial cells, which is consistent with a VEGF mediated angiogenic response. These data indicate that the corneal alkaline burn model of neovascularization is applicable for the development of therapeutic and targeting strategies directed at the avb5 integrin associated neovascular events.
NGF and Corneal Ulcers
Topical application of nerve growth factor (NGF) and amniotic membrane transplantation are two new emerging therapies to treat neurotrophic corneal ulcers. Touhami et al. (p. 987) provide experimental evidence to support that NGF signaling plays a crucial role in maintaining and promoting ex vivo expansion of human limbal epithelial stem cells in amniotic membrane cultures, and that amniotic membrane contains high levels of NGF. These data collectively support the efficacy of topical NGF and amniotic membrane transplantation in treating neurotrophic ulcers. Moreover, they also help explain why amniotic membrane helps expand limbal epithelial stem cells in culture, a new approach that has direct clinical impact in future ocular surface reconstruction.
Mucins and Dry Eye
Mucins are highly O-glycosylated glycoproteins that protect the ocular surface epithelium and may facilitate the stabilization of the tear film. Argüeso et al. (p. 1004) have established methods to quantify conjunctival goblet cell mucin mRNA and protein in impression cytology and tear samples respectively, and have found reduced levels of MUC5AC mucin on the ocular surface of Sjögren’s syndrome patients with dry eye. The loss of mucin in the tear fluid correlates with the reduction in the number of conjunctival goblet cells associated with the disease. Research to ascertain inducers of the MUC5AC gene may provide a new therapeutic approach for dry eye syndromes.
Caspases, APP, and Glaucoma
Retinal ganglion cell death in glaucoma has been shown to occur by the process of programmed cell death, or apoptosis. McKinnon et al. (p. 1077) show that apoptosis-related genes are altered in optic nerve transection and chronic ocular hypertensive rat models of glaucoma. They also find specific activation of the apoptotic proteases caspase-8 and caspase-3 in rat glaucoma models. Abnormal proteolytic processing of amyloid precursor protein (APP), also implicated in the pathogenesis of Alzheimer’s disease, was seen in rodent glaucoma, demonstrating functional similarities between glaucoma and Alzheimer’s disease. Inhibition of caspase activation is a promising therapeutic target for the treatment of glaucoma.
Vitamin E and Prednisolone-Induced Cataract
A long-term examination of lens changes was performed in rats under vitamin E deficient or supplemented conditions (5% Vitamin E Ophthalmic solution, 10 ml/each administration/eye, two times a day) with 1% prednisolone acetate (by eye drop application, 1 mg/kg/day).
After fifteen months, 91.7% of the eyes in the vitamin E deficient+prednisolone administration group had developed anterior and posterior cortical cataracts. As shown in Kojima et al. (p. 1116), supplementation with vitamin E significantly reduced cataract formation (in 38.9% of the eyes). Eye drop application of vitamin E may reduce the cataract risk of prednisolone application.
Antiglaucoma Agents and Flare
Hayasaka et al. (p. 1142) examined the effects of topical instillation of antiglaucoma agents on prostaglandin E2 (PGE2)-induced flare elevation in pigmented rabbits. PGE2, 25mg/ml, was transcorneally applied. Antiglaucoma agent was topically administered before PGE2 application. Aqueous flare was measured with a laser flare-cell meter. Apraclonidine 1.15%, epinephrine 1.25%, and dipivefrine 0.1% eyedrops inhibited flare elevation. Timolol 0.5%, nipradilol 0.25%, dorzolamide 1%, and pilocarpine 2% eyedrops had no effect on flare elevation.
Thioredoxin and Photic Injury
Thioredoxin (TRX) is a small ubiquitous protein with two redox-active half-cystine residues in its active center. TRX has various biological activities as a redox regulator such as activation of transcription factor and regulation of the intracellular apoptotic pathway. Recent information suggests that imbalances in tissue or the cellular redox state are associated with various types of diseases. As recorded in Tanito et al. (p. 1162), TRX is induced in the retinal tissue after light exposure in mice. Intraocular injection of rTRX suppresses retinal photooxidative stress. TRX intensification may be a useful therapeutic strategy to prevent retinal photic injury.
PEDF and Neovascularization
Pigment epithelium-derived factor (PEDF), a neurotrophic factor, has been recently reported as a strong inhibitor of angiogenesis. Ogata et al. (p. 1168) have shown the expression of PEDF in normal rat eyes and in eyes with experimental choroidal neovascularization (CNV). PEDF was observed in cornea, lens epithelial cells, ciliary epithelial cells, retinal ganglion cells, and RPE cells. PEDF was detected in CNV tissues, and prominent expression was observed in RPE cells that proliferated and covered the CNV. These findings suggest that PEDF may play a significant role in the normal rat eye and may modulate the process of choroidal neovascularization.
Zeaxanthin and the Retina
Higher concentrations of carotenoid macular pigments may protect the retina from degenerative changes with aging, but mechanisms regulating their accumulation are unknown. Toyoda et al. (p. 1210) introduce the quail as an experimental model for dietary modification of retinal carotenoids. Zeaxanthin supplementation caused sharp elevations in zeaxanthin concentrations in serum, retina, liver, and fat. The retina captured serum zeaxanthin more efficiently than lutein, while fat captured lutein more efficiently than zeaxanthin. These tissue differences may explain competition between human macula and retina for dietary lutein supplements, and further suggest that macular pigment may be more effectively increased through dietary supplementation with zeaxanthin.
A2E and RPE Cells
A2E, the fluorophore that accumulates in retinal pigment epithelial cells with age and in some retinal disorders, can mediate blue light damage. Sparrow et al. (p. 1222) now show that in response to 430 nm illumination, intracellular A2E undergoes photochemical changes that involve the addition of oxygen molecules. That A2E undergoes photo-oxidation is not only a novel observation, it is also likely to be significant to our understanding of A2E-associated injury to RPE cells.
Haloperidol and Ganglion Cells
Recently haloperidol, an antagonist of dopaminergic D1 and D2 receptors, at a therapeutic dose has been reported to affect PERG which is assumed to reflect the activities of retinal ganglion cell (RGC). Akamine et al. (p. 1257) found that haloperidol did not alter the resting potential of RGCs, but the drug reduced depolarization-activated, voltage-dependent K+ currents at a dose of 100 mM and apamin-sensitive Ca2+-dependent K+ current at a dose of 10 nM. The latter effect of halopridol might explain the alteration of PERG by haloperidol. And these results may indicate the new side effects of haloperidol on visual function.
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