Free Radical Trap Phenyl-N-tert-Butylnitrone Protects against Light Damage But Does Not Rescue P23H and S334ter Rhodopsin Transgenic Rats from Inherited Retinal Degeneration

Abstract

Phenyl-N-tert-butylnitrone (PBN) protects rat retinas against light damage. Because the degenerative process involved in light damage and inherited retinal degeneration both lead to a common final cell death, apoptosis, we used transgenic rats with a P23H or S334ter rhodopsin mutation to test the effects of PBN on retinal degeneration and light damage and the susceptibility of the transgenic rats to light damage. In the first study, 3-week-old mutant and wild-type rats were given no drug, 0.25% PBN in drinking water, or 0.25% PBN in drinking water plus three daily intraperitoneal injections of PBN (100 mg/kg, i.p., every 8 hr). Electroretinograms were recorded at postnatal day 49, after which the rats were killed for morphometric analysis. There was no photoreceptor rescue by PBN in P23H or S334ter rats, as evidenced by equivalent loss of function and photoreceptor cells in the three treatment groups. In the second study, P23H, S334ter, and wild-type rats were exposed for 24 hr to 2700 lux light. The rats were untreated or treated with PBN (50 mg/kg per injection, every 6 hr, starting before exposure). ERGs were recorded before and 1 d after exposure. Animals were killed 6 d later for morphometric analysis. PBN protected wild-type and P23H but not S334ter retinas from light damage. S334ter retinas were relatively less susceptible to light damage than P23H and wild-type rats. The results suggest that the initiating event(s) that causes photoreceptor cell death in the mutated rats is different from that which occurs in light damage, although both ultimately undergo an apoptotic cell death.

Constitutive Overexpression of Human Erythropoietin Protects the Mouse Retina against Induced But Not Inherited Retinal Degeneration

“…Such a prolonged exposure to low-level light may be the cofactor accelerating the degeneration mediated by the VPP mutations. Differences in signaling between light-induced and inherited retinal degeneration are also evidenced by the observed differential effect of several survival factors (LaVail et al, 1998) and other compounds such as nitro-L-arginine methyl ester (Kaldi et al, 2003) or the free radical trap phenyl-N-tert butylnitrone (Ranchon et al, 2003) on lightinduced and inherited retinal degeneration in mice and rats.…”

Probing Mechanisms of Photoreceptor Degeneration in a New Mouse Model of the Common Form of Autosomal Dominant Retinitis Pigmentosa due to P23H Opsin Mutations

“…These results imply that in vivo, a misfolded monomer of P23H opsin can also induce co-aggregation with WT rhodopsin preventing rod outer segment (ROS) formation. This dominant negative effect on ROS formation has been considered as the underlying reason for the adRP inheritance of P23H in humans.The retinal structure in heterozygous transgenic mice and rats expressing the P23H opsin partially mimics that of adRP in humans carrying this mutation (15)(16)(17)(18)(19). Mislocalization of the P23H opsin in the retina also has been reported in transgenic animal models (20), and this causes an abnormally reduced response to light (21).…”

“…The retinal structure in heterozygous transgenic mice and rats expressing the P23H opsin partially mimics that of adRP in humans carrying this mutation (15)(16)(17)(18)(19). Mislocalization of the P23H opsin in the retina also has been reported in transgenic animal models (20), and this causes an abnormally reduced response to light (21).…”

Cytoprotective Effects of Geranylgeranylacetone against Retinal Photooxidative Damage

“…Light exposure induces photoreceptor cell death via apoptosis (Hafezi et al, 1997;Wenzel et al, 2000). Free radicals, including reactive oxygen species, play a crucial role in the damage (Organisciak et al, 1989;Ranchon et al, 2003).…”