OT-551

OT-551 (1-hydroxy-4-cyclopropanecarbonyloxy-2,2,6,6-tetramethylpiperidine hydrochloride), is a novel small molecule with antioxidant and anti-inflammatory effects. Protective efficacy of OT-551 and its metabolite TEMPOL-H (TP-H) against light-induced degeneration of retinal pigment epithelium (RPE) was tested. Albino rats were intraperitoneally injected with OT-551, TP-H, or water approximately 30 min prior to a 6 h exposure to 2700 lux white fluorescent light. Retinal protection was evaluated histologically by counting the RPE cell nuclei and measuring the extent of RPE damage on the retinal sections as RPE damage index (%). Following light exposure, the number of RPE cell nuclei was significantly reduced in light-exposed eyes from water-treated animals, while the number was not significantly different between light-exposed and unexposed eyes from the animals treated with 100 mg/kg TP-H or with any dose of OT-551 in the inferior hemisphere, and with 100 mg/kg OT-551 in the superior hemisphere. RPE damage index was significantly lower in the animals treated with any dose of OT-551 compared to water-treated animals both in the inferior and superior hemispheres. Systemic administration of OT-551 and TP-H provides RPE cell protection against acute light damage, and the protection by OT-551 was greater than by TP-H.

OT-551 (1-hydroxy-4-cyclopropanecarbonyloxy-2,2,6,6-tetramethylpiperidine hydrochloride), a TEMPOL-H (OT-674) derivative, is a new catalytic antioxidant. In the present study, the efficacy of OT-551 and OT-674 in retinal neuroprotection was tested in a model of light-induced photoreceptor degeneration.

Albino rats were intraperitoneally injected with OT-551, OT-674, or water, approximately 30 minutes before a 6-hour exposure to 2700-lux white fluorescent light. Retinal protection was evaluated histologically by measuring the thickness of the outer nuclear layer (ONL) and functionally by electroretinogram (ERG) analysis, 5 to 7 days after exposure to light. Levels of protein modification by 4-hydroxynonenal (4-HNE) and 4-hydroxyhexenal (4-HHE), which are end products of the nonenzymatic oxidation of n-6 and n-3 polyunsaturated fatty acids, respectively, were measured by Western dot blot analysis immediately after exposure to light.

After exposure to light, water-treated animals had a 77% loss of ERG b-wave amplitudes and a 26% and 56% loss of mean ONL thickness in the inferior and superior hemispheres, respectively. Compared with water-treated rats, ERG b-wave amplitudes in light-exposed eyes were significantly higher in 25 (P < 0.05)-, 50 (P < 0.05)-, and 100 (P < 0.001)-mg/kg OT-551-treated rats. Mean ONL thickness in the superior hemisphere was significantly higher in 25 (P < 0.01)-, 50 (P < 0.01)-, and 100 (P < 0.001)-mg/kg OT-551-treated, light-exposed eyes and in 100 mg/kg (P < 0.05) OT-674-treated eyes. No decrease of ONL thickness was observed in the light-protected covered fellow eyes in any animal. Increased levels of 4-HNE- and 4-HHE-protein modifications after exposure to light in water-treated eyes were completely counteracted by 100 mg/kg OT-551.

Systemic administration of OT-551 and OT-674 provides both functional and morphologic photoreceptor cell protection against acute light-induced damage, most likely by inhibiting lipid peroxidation. The protection by OT-551 was greater than OT-674.