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S. B. Smith, G. Jiang, B. Mysona, A. Martin-Studdard, P. Roon, V. Ganapathy; The Sigma Receptor-1 (R1) Ligand Pentazocine (PTZ) Affords Marked Protection Against Neuronal Degeneration in the Ins2Akita Mouse Model of Retinopathy. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1541.
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Neurodegenerative diseases, such as glaucoma and diabetic retinopathy, result in progressive loss of retinal neurons and their processes. Mice heterozygous (+/-) for the Ins2Akita mutation develop hyperglycemia, hypoinsulinemia and marked loss of retinal neurons (Barber et al, 2005). In this study, Ins2Akita mice were used as a model to test the in vivo neuroprotective properties of (+)-pentazocine (PTZ), a ligand for sigma receptor-1 (σR1). σR1 is a nonopiate, nonphencyclidine binding site with robust neuroprotective properties.
Founder C57BL/6J Ins2Akita mice were bred in our colony. Male +/- offspring become diabetic at ~3 wks postnatally and were used for analysis at 6, 10 and 17 weeks postnatally compared to age-matched wild-type (+/+) mice. Eyes were harvested and retinas subjected to comprehensive morphometric analysis using the Zeiss AxioVision program to determine total retinal thickness, thicknesses of inner/outer nuclear and plexiform layers (INL, ONL, IPL, OPL) and the number of ganglion cells (RGCs) per 100 µm length of retina. A second group of +/- and +/+ Ins2Akita mice received intraperitoneal injections of PTZ (0.5 mg/kg, 2 times/week) beginning at diabetes onset and retinas were analyzed morphometrically 25 weeks postnatally.
Ins2Akita +/- mice showed marked disruption of retinal architecture. By 17 weeks postnatally, they demonstrated 12% and 19% decreases in IPL and OPL thicknesses, respectively, a 17% decrease in INL thickness and in INL cell number, and a 25% reduction in RGCs. In the PTZ treated group, retinas of Ins2Akita +/- mice showed remarkable preservation of normal retinal architecture. Morphometric analysis confirmed that IPL, OPL, INL thicknesses of PTZ-treated Ins2Akita +/- mouse retinas were within normal limits. The number of RGCs was 15.9 ± 0.89 cells vs. 10.4 ± 1.8 cells per 100 µm length of retina in PTZ-treated vs. non-treated mice, respectively.
The Ins2Akita mouse is a very useful model of retinal neuronal degeneration. Sustained treatment of these mice with the σR1 ligand PTZ provided significant neuroprotection making it an extremely promising therapeutic agent for intervention in neurodegenerative diseases of retina.
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