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Hiroshi Tomita, Yashige Kotake, Robert E. Anderson; Mechanism of Protection from Light-Induced Retinal Degeneration by the Synthetic Antioxidant Phenyl-N-tert-Butylnitrone. Invest. Ophthalmol. Vis. Sci. 2005;46(2):427-434. doi: 10.1167/iovs.04-0946.
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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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