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S. B. Smith, J. N. Duplantier, P. Roon, Y. Dun, B. Mysona, V. Ganapathy; Oxidative Stress Is Attenuated in Retinas of Ins2Akita Diabetic Mice Following Treatment With (+)-Pentazocine A Sigma Receptor-1-Specific Ligand. Invest. Ophthalmol. Vis. Sci. 2008;49(13):4921. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Recently, we reported that administration of the sigma receptor-1 (σR1) ligand (+)-pentazocine ((+)-PTZ) preserved retinal architecture and significantly decreased neuronal apoptosis in the Ins2Akita mouse model of diabetic retinopathy (Smith et al, ARVO 2007). Reactive oxygen species and reactive nitrogen species have been implicated in the pathogenesis of diabetic retinopathy; ligands for σR1 have been shown to protect against both types of stress. In the present study we examined the effects of (+)-PTZ on expression of markers for oxidative stress in retinas of Ins2Akita mice.
Ins2Akita +/- and +/+ (WT) mice received intraperitoneal injections of (+)-PTZ (0.5 mg/kg, 2 times/week) for 22 weeks beginning at diabetes onset. Retinal cryosections were prepared and subjected to immunohistochemistry using antibodies specific for 4-hydroxynonenal (4-HNE) and nitrotyrosine, markers of lipid peroxidation and reactive nitrogen species, respectively. Sections were examined by immunofluorescence and data were compared to that obtained from age-matched, untreated Ins2Akita +/- and +/+ mice. Western blotting was performed using these same antibodies with protein isolated from neural retinas of these mice. Additional cryosections were immunolabeled with an antibody specific for vimentin to view the radial Müller fibers in PTZ-treated and untreated diabetic mice retinas.
Levels of nitrotyrosine and 4-HNE were increased in Ins2Akita +/- retinas, but were reduced markedly in mice maintained on (+)-PTZ. Western blotting confirmed these results. Retinas of Ins2Akita +/- mice showed marked disruption of retinal architecture as evidenced by loss of the radial-labeling of Müller fibers; retinas of (+)-PTZ-treated mice maintained the typical radial organization of glial processes.
There was a significant reduction in expression of markers of oxidative stress in retinas of diabetic Ins2Akita when maintained on (+)-PTZ throughout the period of diabetes. Retinal architecture, as evidenced by excellent organization of radial glial fibers, was preserved in (+)-PTZ-treated Ins2Akita mice. When administered immediately at diabetes onset, the σR1 ligand (+)-PTZ appears to attenuate markedly oxidative damage characteristic of diabetic retinopathy and may be a very useful therapeutic agents for intervention in this disease.
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