Retinitis pigmentosa (RP) is a group of devastating inherited retinal diseases that leads to visual impairment and oftentimes complete blindness. Currently no cure exists for RP thus research into prolonging vision is imperative. Sigma 1 receptor (Sig1R) is a promising small molecule target that has neuroprotective benefits in retinas of rapidly-degenerating mouse models. It is not clear whether Sig1R activation can provide similar neuroprotective benefits in more slowly-progressing RP models. Here, we examined Sig1R-mediated effects in the slowly-progressing Rho mouse, a model of autosomal dominant RP. We characterized the retinal degeneration of the Rho mouse over a 10 month period using three in vivo methods: Optomotor Response (OMR), Electroretinogram (ERG), and Spectral Domain-Optical Coherence Tomography (SD-OCT). A slow retinal degeneration was observed in both male and female Rho mice when compared to wild type. The OMR, which reflects visual acuity, showed a gradual decline through 10 months. Interestingly, female mice had more reduction in visual acuity than males. ERG assessment showed a gradual decline in scotopic and photopic responses in Rho mice. To investigate the neuroprotective benefits of Sig1R activation in the Rho mouse model, mutant mice were treated with a high-specificity Sig1R ligand (+)-pentazocine ((+)-PTZ) 3x/week at 0.5mg/kg and examined using OMR, ERG, SD-OCT. A significant retention of visual function was observed in males and females at 10 months of age, with treated females retaining ∼50% greater visual acuity than non-treated mutant females. ERG revealed significant retention of scotopic and photopic b-wave amplitudes at 6 months in male and female Rho mice treated with (+)-PTZ. Further, in vivo analysis by SD-OCT revealed a significant retention of outer nuclear layer (ONL) thickness in male and female treated Rho mice. Histological studies showed significant retention of IS/OS length (∼50%), ONL thickness, and number of rows of photoreceptor cell nuclei at 6 months in (+)-PTZ-treated mutant mice. Interestingly, electron microscopy revealed preservation of OS discs in (+)-PTZ treated mutant mice compared to non-treated. Taken collectively, the in vivo and in vitro data provide the first evidence that targeting Sig1R can rescue visual function and structure in the Rho mouse. These results are promising and provide a framework for future studies to investigate Sig1R as a potential therapeutic target in retinal degenerative disease.
Copyright © 2023. Published by Elsevier Ltd.