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Haiyan Xiao, Jing Wang, Sylvia B Smith; Comparison of Sigma 1 Receptor (Sig1R) ligands SA4503, PRE084 and (+)-pentazocine ((+)-PTZ) for their cone photoreceptor (PRC) rescue effects in the Pde6brd10/J (rd10) mouse model of retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2020;61(7):1288.
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© ARVO (1962-2015); The Authors (2016-present)
Sig1R, a pluripotent modulator of cell survival is a promising target for treatment of retinopathies. Our previous work demonstrated that activating Sig1R using the high-affinity, high-specificity Sig1R ligand (+)-PTZ rescues cone PRCs in the rd10 mouse (Wang et al, PNAS, 2016). Here we investigated whether activation of Sig1R using ligands SA4503 (Ki = 4.6 nM) & PRE084 (Ki = 2.2 nM) would afford cone rescue in rd10 mice comparable to that observed with (+)-PTZ treatment.
In vitro: 661W cells were treated with SA4503 or PRE084 [50 or 100 µM] to assess cell viability, expression of Nrf2 & antioxidant genes it regulates (Nqo1, Cat, Sod1), and effects on tBHP-induced oxidative stress using the CellROX assay. In vivo: rd10 mice (n=4-7/group) were administered either (+)-PTZ [0.5mg/kg], SA4503 [1 mg/kg], or PRE084 [0.5mg/kg] IP beginning P14 & continuing every other day through P42. Visual acuity was assessed by OKR, retinal integrity by OCT, electrophysiologic function by ERG; eyes were harvested at P42 to evaluate PRC nuclei remaining in the outer nuclear layer. Data were compared to non-treated rd10 & WT mice.
In vitro: Exposure of 661W cells to SA4503 & PRE084 improved viability, increased Nrf2, Nqo1, Cat, Sod1 expression & attenuated tBHP-induced oxidative stress significantly, similar to (+)-PTZ treatment. In vivo: Visual acuity improved significantly in (+)-PTZ-treated mice (0.3c/d), but was only slightly greater with SA4503 (0.15 c/d) or PRE084 (0.13 c/d) v. non-treated rd10 mice (0.11c/d). By OCT, outer retinal thickness was ~20µm in SA4503- & PRE084-treated, which was similar to non-treated rd10 mice; whereas it was ~35nm in (+)-PTZ-treated mice. Photopic b-wave amplitudes were increased in (+)-PTZ-treated rd10 mice, but not in other groups. Regarding number of PRC nuclei: rd10, SA4503- & PRE084-treated mice had 12.2±0.3,14.3±0.1, 13.6±0.1/100µm retinal length, respectively; (+)-PTZ-treated mice had significantly more (22.7±0.2/100µm).
Our data suggest that SA4503 & PRE084 are neuroprotective in vitro, but do not afford in vivo protection against catastrophic cone PRC loss in rd10 mice as effectively as the highly specific ligand (+)-PTZ, raising important questions about selection of the best Sig1R ligand for future therapeutic strategies.
This is a 2020 ARVO Annual Meeting abstract.
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