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(Investigative Ophthalmology and Visual Science. 2006;47:3178-3186.)
© 2006 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-1370
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The ß-Adrenergic Receptor Antagonist Metipranolol Blunts Zinc-Induced Photoreceptor and RPE Apoptosis

Neville N. Osborne and John P. M. Wood

From the Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom.

PURPOSE. To determine the effect of zinc on retinal cells at concentrations at which it is known to cause oxidative stress. Furthermore, the effects of metipranolol, known to prevent retinal damage, and of other antiglaucoma drugs were determined on zinc-injured retinal cells.

METHODS. Lipid peroxidation assays were conducted on rat brain and bovine retina–retinal pigment epithelial (RPE) membrane preparations. Immunohistochemistry, immunoblot analysis and the terminal-deoxynucleotidyl transferase dUTP-linked nick-end labeling (TUNEL) procedure determined the effects of zinc with or without trolox or metipranolol on photoreceptor death in situ. The effect of treatments on cultured RPE cells was analyzed using cell viability assays, immunoblot analysis, and the TUNEL procedure.

RESULTS. Zinc-induced lipid peroxidation of rat brain and bovine retina–RPE membranes, although the effect of the latter was of a (twofold) greater magnitude. Both effects, however, were similarly attenuated by metipranolol, desacetylmetipranolol, and trolox. Antiglaucoma drugs other than metipranolol had no effect. Intraocular injection of 150 µM zinc and treatment of cultured RPE cells with zinc led to mainly photoreceptor apoptosis and apoptotic death of RPE cells (50% death at 18 µM rising to 10% at 50 µM), respectively. Zinc-induced apoptosis of cultured RPE cells and photoreceptors were attenuated only by metipranolol and trolox.

CONCLUSIONS. The combined data suggest that oxidative injury to RPE cells and photoreceptors may be caused by elevated levels of zinc in diseases such as age-related macular degeneration (AMD) and that metipranolol may act as an efficacious antioxidant to blunt this process.




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K. A. Rezaei, Y. Chen, J. Cai, and P. Sternberg
Modulation of Nrf2-Dependent Antioxidant Functions in the RPE by Zip2, a Zinc Transporter Protein
Invest. Ophthalmol. Vis. Sci., April 1, 2008; 49(4): 1665 - 1670.
[Abstract] [Full Text] [PDF]


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