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(Investigative Ophthalmology and Visual Science. 2004;45:1523-1530.)
© 2004 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-1315
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Protection by Pyruvate of Rat Retinal Cells against Zinc Toxicity In Vitro, and Pressure-Induced Ischemia In Vivo

Min Heui Yoo,1,2 Joo-Yong Lee,2,3 Song Eun Lee,3 Jae-Young Koh,1,4 and Young Hee Yoon3

1From the Creative Research Initiative Center for the Study of CNS Zinc and 3the Departments of Ophthalmology and 4Neurology, University of Ulsan College of Medicine, Seoul, Korea.

PURPOSE. To examine whether zinc accumulation occurs during retinal neuronal death after pressure-induced ischemia in rats and whether pyruvate protects against such death.

METHODS. To induce transient retinal ischemia, intraocular pressure was increased above systolic pressure for 65 minutes. Pyruvate was administered through the tail vein for 12 hours after ischemia to determine its effect on degeneration of retinal neurons. Retinas were removed and sectioned, and zinc accumulation was visualized with N-(6-methoxy-8-quinolyul)-p-carboxybenzoyl-sylphonamide (TFL-Zn) fluorescence microscopy, and neuronal death was determined with acid fuchsin staining. For in vitro studies, retinal cell cultures were prepared from newborn rat pups and used for experiments at days in vitro (DIV) 7 to 10.

RESULTS. After retinal ischemia, staining revealed that most zinc-accumulating neurons were injured neurons, suggesting that endogenous zinc may contribute to ischemic neuronal death in the retina. In vitro studies showed that 15 minutes of exposure to 300 to 500 µM zinc resulted in the death of a substantial number of retinal cells in culture, and that this death was preceded by poly(ADP-ribose) polymerase (PARP)-mediated depletion of nicotinamide-adenine dinucleotide (NAD+) and adenosine triphosphate (ATP). Pyruvate, but not lactate, protected against this zinc-induced cell death in vitro. Consistent with this finding, in vivo studies showed that compared with control rats, pyruvate-treated rats had a substantial reduction in the number of cells showing signs of cell death.

CONCLUSIONS. The present results suggest endogenous zinc contributes to retinal cell death after ischemia. Pyruvate potently protected against zinc toxicity in cultured rat retinal cells and reduced ischemia-induced cell death in rat retinas.






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