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1From the Lions Eye Institute, The Centre for Ophthalmology and Visual Science, The University of Western Australia, Perth, Australia; the 2Retinal Dystrophy Research Centre, Department of Anatomy and Histology and Institute for Biomedical Research, University of Sydney, Sydney, Australia; and the 3Research School of Biological Science, Australian National University, Canberra, Australia.
PURPOSE. To relate the oxygen environment of the retina to photoreceptor stability, protection, and function in the P23H rat.
METHODS. Heterozygote P23H-3 (Line 3) rats were studied. Photoreceptor death rates were assessed with the TUNEL technique for detection of fragmenting DNA, in a developmental series from postnatal day (P)16 to P105 (adult). In adult retinas, trophic factor status was assessed with immunohistochemistry, intraretinal oxygen environment with O2-sensing electrodes, and photoreceptor function by the flash-evoked, dark-adapted electroretinogram (ERG), recorded in anesthetized animals.
RESULTS. Photoreceptor death begins by P16; peaks at P25, when the frequency of TUNEL+ profiles exceeds 70/mm of retina; and then declines to low (<5/mm) adult rates. Compared with that in nondegenerative Sprague-Dawley (SD) rats, the rate of photoreceptor death is abnormally high from P16 and remains several-fold higher than normal into young adulthood. In addition, the outer nuclear layer is reduced to approximately half of control thickness, and the levels of ciliary neurotrophic factor (CNTF), glial fibrillary acidic protein (GFAP), fibroblast growth factor (FGF)-2, and FGF-2/FGFR1 colocalization are markedly upregulated. O2 tension and uptake are relatively normal in the inner retina, but uptake is considerably reduced, and O2 tension is significantly raised in the outer retina. Surviving photoreceptors generate an a-wave with normal peak latency but sharply reduced amplitude.
CONCLUSIONS. Excess photoreceptor degeneration in the P23H-3 retina begins just after eye opening, peaks in early postnatal life, and then slows, but persists into adulthood. In the adult retina, surviving photoreceptors operate in an environment that is chronically hyperoxic (and therefore toxic) and in which protective factors (CNTF, FGF-2) are chronically upregulated. The net result, slow degeneration and degraded function in an environment that is both toxic and protective, may be representative of adult photoreceptor status in a number of human retinal degenerations. Hyperoxia-induced photoreceptor death may be a self-reinforcing factor that increases oxidative stress in surviving photoreceptors.
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