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| October 2002 | Inside IOVS | Volume 43/10 |
| Basic Science Advances in Treating Ocular Diseases |
HClO/OCl- Suppresses Corneal Inflammation
In response to injury, activated neutrophils release TNFa and myeloperoxidase. TNFa in turn causes human corneal epithelial cells to secrete interleukin 1a (IL-1a) whereas MPO results in HClO/OCl- formation. Mohri et al. (p. 3190) show that HClO/OCl- oxidizes IkBa at methionine residues, decreases IkBa dissociation from NFkB and thereby suppresses TNFa induced increase in IL-1a secretion. This finding indicates that release of HClO/OCl- in vivo by activated neutrophils may counterbalance TNFa induced NFkB-dependent IL-1a secretion and thereby suppress an excessive inflammatory reaction. Furthermore, this finding also indicates that methionine redox may play an important role in cell signal transduction.
Implantable Contact Lenses
Current trends in refractive surgery are directed towards the consumer demands for permanent correction of refractive error without the need for external devices such as spectacles and conventional contact lenses. The Cooperative Centre for Eye Research and Technology in Sydney has developed a perfluoropolyether-based polymer for use as an implantable contact lens (synthetic corneal onlay). Evans et al. (p. 3196) report the clinical and histological findings following implantation of this polymer in feline corneas for up to 8 weeks. If successful, this technology offers an alternative approach to refractive correction using an adjustable and reversible procedure with minimal surgical intervention of the central optical zone.
Endocannabinoids and IOP
Laine et al. (p. 3216) reported that the novel endocannabinoid, noladin ether, which was recently identified in porcine and rat brains, decreases IOP in rabbits after its ocular administration. Earlier studies have demonstrated the IOP lowering effects of endogenous CB1 receptor ligands, AEA and 2-AG. Interestingly, the mechanism of action of noladin ether differs from that of AEA and 2-AG; noladin ether decreases IOP directly via CB1 receptors, whereas both AEA and 2-AG most probably act via their arachidonic acid based prostanoid metabolite(s).
Endothelins and Glaucoma
Increases in aqueous endothelin-1 have been associated with glaucoma, perhaps in response to elevated IOP and/or retinal ischemia. Stokely et al. (p. 3223) demonstrated that intravitreal administration of endothelin-1 induces extended periods (4 hours to 21 days) of aberrant anterograde axonal transport in the rat optic nerve. Effects were most pronounced at times known to be associated with normal anterograde transport of mitochondrial marker proteins (28-36 hours). The ETB receptor-selective agonist ET-3 mimicked ET-1’s effect (28 hours, time of maximal effect), suggesting an ETB-mediated event. Stokely et al. propose the hypothesis that endothelins may serve as pathogenic intermediaries between the common risk factors for glaucoma and glaucomatous optic neuropathy.
Microarrays and Lens Oxidative Stress
Oxidative Stress is recognized as a major factor in the development of maturity onset cataract (MOC). To find antioxidative defense genes (ADG) that may prevent MOC, the Spector laboratory prepared conditioned cell lines that survive peroxide stress at concentrations that cause cataract. Now using Affymetrix micro-arrays, Spector et al. (p. 3251) have examined 12,422 genes from these cell lines. Twenty seven ADGs have been identified with significant change in gene expression. They include few of the classical ADGs. Among the identified genes are members of the GSH-S-transferase family, catalase, NADPH menadione oxidoreductase 1 and hephaestin. The group now plans to determine whether one or more of these genes will protect the lens from peroxide stress and perhaps prevent MOC.
Proteolysis and Diabetic Cataract
aA- and aB-crystallins are molecular chaperones with the ability to suppress protein aggregation. Probably due to increased posttranslational modifications the chaperone function of a-crystallin is affected in diabetic lenses. In diabetic human and rat lenses, Thampi et al (p. 3265) have shown significantly increased levels of the products of proteolysis of C-terminal residues forming truncated aA- and aB-crystallins.There is evidence for specific activation in diabetes of m-calpain, a key protease in the lens. Since truncated a-crystallins have decreased chaperone activity, enhanced proteolysis of a-crystallin could be a significant factor in cataract development in diabetes.
Dorzolamide and Corneal Endothelial Cells
This study by Srinivas et al. (p. 3273) shows that dorzolamide, a topical drug used to reduce intraocular pressure in glaucoma therapy, significantly inhibits carbonic anhydrase activity in cultured bovine corneal endothelial cells at micromolar levels. Since these levels are encountered in the cornea and aqueous humor upon its topical administration in human eyes, corneal hydration control may be compromised when the functional reserve of corneal endothelium is low.
Encapsulated Cell Technology (ECT) in Ophthalmic Disorders
Tao et al. (p. 3292) have developed a novel ECT device specifically for intra-ocular implantation. The cell-containing device secretes therapeutic factors directly into the vitreous, bypassing the blood-retina barrier, and enabling controlled, continuous, long-term delivery of a variety of proteins. Encapsulated human mammalian cell line that was genetically engineered to secrete recombinant human CNTF was used in well-characterized animal models for retinitis pigmentosa. Cell-based CNTF delivery demonstrated a clear and significant dose-dependent protection from photoreceptor degeneration, without adverse effects on the retina. These results suggest that encapsulated cell therapy may provide a safe and effective strategy for treating ophthalmic disorders in humans.
CCI in Topical Ocular Drug Delivery
As reported in Voigt et al. (p. 3299), a comparison of iv, topical and CCI administration of ASA demonstrated that the application of CCI resulted in higher ocular tissue concentrations. CCI is a non-invasive, topical drug administration using current to enforce the migration of drug molecules through tissue barriers. Classical, systemic iv drug administration resulted in low ocular tissue concentrations. The potential benefit of CCI could be seen in the treatment of chronic inflammatory disease, uvietis and cysloid macular edema.
BDNF Signaling in the Retina
The effectiveness of BDNF for the neuroprotection of retinal ganglion cell has been demonstrated in various retinal injury models, although the signaling mechanism of BDNF-mediated neuroprotection remains unclear. We previously showed that the neural-specific phosphotyrosine adapter N-Shc/ShcC functioned immediate downstream of TrkB and was a key signaling adapter toward Ras-MAPK by BDNF in the retina. Nakazawa et al. (p. 3319) determined here the relative contribution of two major signaling pathways, i.e., Ras-MAPK and PI3K-Akt routes, as to neuroprotection following axotomy. Our data demonstrates that both pathways are equally active, suggesting that collaboration of these pathways is necessary in the neuroprotection signaling of BDNF in the retina.
PAF in Microvascular Degeneration
Degeneration of the microvasculature is a significant feature of ischemic retinopathies, resulting in functional deficits as well as predisposing to neovascularization. Platelet activating factor (PAF) and thromboxane (TXA2) are pro-inflammatory mediators readily released under conditions of oxidant stress. Beauchamp et al. (p. 3327) have uncovered a major role for PAF in retinal microvascular degeneration in a model of oxidant stress, independent of inflammatory cells; PAF evokes direct cytotoxicity specifically to neurovascular endothelial cells via a TXA2-mediated mechanism. These unprecedented findings may have important implications for microvascular degeneration associated with retinopathy of diabetes and prematurity, and thus provide new therapeutic targets for ischemic retinopathies.
Ribozymes and PVR
Proliferating cell nuclear antigen (PCNA) is a critical cell cycle regulatory protein and is important in the proliferative response seen in PVR. The period of active proliferation in PVR is short, therefore, ribozyme targeting PCNA that is introduced into the vitreous cavity may prove to be a novel treatment for the disease. Mandava et al. (p. 3338) establish the efficacy of a chimeric ribozyme to PCNA with and without lipid vehicle in the treatment of PVR in a rabbit model. The benefit of the ribozyme is seen in both the prevention as well as in the treatment of established disease. The oligonucleotide shows stability in vitreous and demonstrates uptake in fibroblasts. An effective dose of naked ribozyme was established for clinical use. A clinical trial is underway to assess its safety and potential for efficacy in patients with PVR.
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