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Mechanism of Protection from Light-Induced Retinal Degeneration by the Synthetic Antioxidant Phenyl-N-tert-Butylnitrone

¹From the Departments of Ophthalmology and ⁴Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; ²Dean A. McGee Eye Institute, Oklahoma City, Oklahoma; and ³Free Radical Biology and Aging Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma.

PURPOSE. A prior study demonstrated that pretreatment with phenyl-N-tert-butylnitrone (PBN), a synthetic antioxidant and free radical trapping agent, protects rats from light-induced photoreceptor cell death. The objective of the present study was to elucidate the molecular mechanism of PBN neuroprotection.

METHODS. Sprague-Dawley rats (5–6 weeks old) raised in dim (5 lux) cyclic light (12 hours ON/OFF) from birth were injected intraperitoneally with PBN or water 30 minutes before exposure to three columns of fluorescent light (2700 lux intensity) for 0, 3, 6, 12, or 24 hours. mRNA levels were measured by RNase protection assay and DNA fragmentation by TUNEL assay. Activator protein (AP)-1 complex was determined by electrophoretic mobility shift assay. Immunocytochemistry and Western blots were used to measure changes in c-fos levels.

RESULTS. Typical apoptotic features (TUNEL staining and DNA laddering) were seen in rat retinas after 24 hours of continuous exposure to light, but not in PBN-injected rats. FasL, Bax, and caspase-3 were upregulated in a time-dependent manner. PBN treatment markedly inhibited caspase-3 gene expression, but neither PBN nor bright light exposure had any effect on caspase-3 activity. AP-1 activation by exposure to light was inhibited by PBN. Western blot analysis showed that the c-fos protein level increased in the nuclear fraction after a 6-hour exposure to light, but was decreased in PBN-treated rats.

CONCLUSIONS. Inhibition of c-fos activation by PBN may be the key event in protection. The involvement of oxygen free radicals has been suggested in c-fos activation and the action of PBN could be through its antioxidant activity.

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