Protective effect of TEMPOL derivatives against light-induced retinal damage in rats.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Tanito
Masaki
M
Department of Ophthalmology, University of Oklahoma Health Sciences Center, 608 S.L. Young Boulevard, Oklahoma City, OK 73104, USA. tanito-oph@umin.ac.jp
Li
Feng
F
Elliott
Michael H
MH
Dittmar
Mark
M
Anderson
Robert E
RE
D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000627:therapeutic use*; D004596:Electroretinography / Q000528:radiation effects; D019811:Hydroxylamine / Q000008:administration & dosage / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D008027:Light; D015227:Lipid Peroxidation / Q000187:drug effects; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000503:physiopathology / Q000528:radiation effects*; D012162:Retinal Degeneration / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013113:Spin Labels
D000447:Aldehydes; D003497:Cyclic N-Oxides; D013113:Spin Labels; D019811:Hydroxylamine; C027576:4-hydroxy-2-nonenal; C001803:tempol; C505333:TEMPOL-H