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Jing Wang, Alan Saul, Vadivel Ganapathy, Sylvia B Smith; (+)-Pentazocine ((+)-PTZ), a high affinity sigma 1 receptor (σ1R) ligand preserves cone function in the Pde6rd10 (Rd10) mouse model of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5475.
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© ARVO (1962-2015); The Authors (2016-present)
σ1R, a unique transmembrane protein located at the ER, mitochondria, nuclear and plasma membranes, has retinal neuroprotective properties in vitro (primary RGCs, Mueller et al, 2014; Dun et al 2007) and in vivo (Ins2Akita/+ diabetic mouse, Smith et al, 2008). We asked whether (+)-PTZ, a high-affinity σ1R ligand, could attenuate rod-cone degeneration in Pde6rd10 mice, which demonstrate rapid, profound photoreceptor (PRC) loss.
Pde6rd10 mice were injected i.p with (+)-PTZ (0.5 mg · kg−1) every other day beginning at P14. Mice were subjected to ERG and OCT at P35. At P42, eyes were enucleated, cryosectioned & subjected to TUNEL assay to evaluate apoptosis; morphometric analysis to assess PRC loss and immunohistochemistry (IMH) to examine rods (anti-rhodopsin), cones (anti-cone-arrestin), rod bipolar cells (anti-PKCα) and Müller cell activation (anti-GFAP). One-way ANOVA was used to compare Pde6rd10 data to that of age-matched wild type (WT) and non-injected-Pde6rd10 mice.
ERG showed partial rescue of scotopic (rod) responses in (+)-PTZ-injected versus non-injected-Pde6rd10 mice and significant rescue of photopic (cone) responses, especially b-wave amplitude (~50% of WT mice - compared to virtually no response in non-injected-Pde6rd10 mice). Remarkably, ERG using low temporal frequencies (natural noise), mediated almost entirely by cones, showed similar strength responses in (+)-PTZ-injected mice versus WT. OCT revealed greater retinal thickness in (+)-PTZ-injected versus non-injected Pde6rd10 mice, which was confirmed by morphometric analysis: WT: 203.03±36.22 µm; Pde6rd10: 84.02±35.65 µm; (+)-PTZ-injected-Pde6rd10: 115.99±28.59 mm. The number of PRC rows was significantly greater in (+)-PTZ-injected (2.3±1.1) versus non-injected Pde6rd10 mice (0.96±0.6). The number of TUNEL positive PRCs per retina section was markedly reduced in (+)-PTZ-injected (5.3±2.0) versus non-injected Pde6rd10 mice (32.8±15.6). IMH showed preservation of cones and bipolar cells and decreased Müller cell GFAP levels in (+)-PTZ-injected versus non-injected-Pde6rd10 mice.
This is the first in vivo attempt targeting σ1R for treatment of severe retinopathy. (+)-PTZ administration preserved cone function in Pde6rd10 mice suggesting that σ1R activation may offer a novel, highly promising therapeutic strategy for severe retinal degenerations.
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