Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, Georgia, United States.
James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States.
Invest Ophthalmol Vis Sci. 2020 Nov 2;61(13):3. doi: 10.1167/iovs.61.13.3.
Sigma 1 receptor is a novel therapeutic target for retinal disease. Its activation, using a high-affinity, high-specificity ligand (+)-pentazocine ((+)-PTZ), rescues photoreceptor cells in the rd10 mouse model of RP. Here, we asked whether the robust retinal neuroprotective properties of (+)-PTZ are generalizable to SA4503 and PRE084, two other high-affinity sigma 1 receptor ligands.
We treated 661W cells with SA4503 or PRE084. Cell viability, oxidative stress, and expression of Nrf2 and NRF2-regulated antioxidant genes (Nqo1, Cat, and Sod1) were assessed. Rd10 mice were administered SA4503 (1 mg/kg), PRE084 (0.5 mg/kg), or (+)-PTZ (0.5 mg/kg). Visual acuity, retinal architecture, and retinal electrophysiologic function were measured in vivo and retinal structure was assessed histologically.
Similar to (+)-PTZ, SA4503 and PRE084 improved cell viability, attenuated oxidative stress, and increased Nrf2, Nqo1 and Cat expression. Although treatment of rd10 mice with (+)-PTZ improved visual acuity, increased outer retinal thickness, and improved photopic a- and b-wave responses compared with nontreated rd10 mice, treatment with SA4503 or PRE084 did not. The number of photoreceptor nuclei/100 µm retinal length in SA4503- and PRE084-treated rd10 mice (approximately 11/100) did not differ significantly from nontreated rd10 mice, whereas (+)-PTZ-treated mice had significantly more nuclei (approximately 22/100 µm).
Cell survival and gene regulation experiments yielded similar outcomes when SA4503, PRE084, or (+)-PTZ were conducted in vitro, however neither SA4503 or PRE084 afforded in vivo protection in the severe rd10 retinopathy model comparable to (+)-PTZ. Despite all three compounds demonstrating the potential to activate sigma 1 receptor, the retinal neuroprotective properties of the three ligands differ significantly.
西格玛 1 受体是视网膜疾病的一种新的治疗靶点。其激活剂，使用高亲和力、高特异性配体(+)-戊噻嗪((+)-PTZ)，可挽救 rd10 型 RP 小鼠模型中的光感受器细胞。在这里，我们想知道 (+)-PTZ 的强大的视网膜神经保护特性是否可以推广到 SA4503 和 PRE084，这两种其他高亲和力西格玛 1 受体配体。
我们用 SA4503 或 PRE084 处理 661W 细胞。评估细胞活力、氧化应激以及 Nrf2 和 NRF2 调节的抗氧化基因（Nqo1、Cat 和 Sod1）的表达。给 rd10 小鼠施用 SA4503（1mg/kg）、PRE084（0.5mg/kg）或(+)-PTZ（0.5mg/kg）。体内测量视敏度、视网膜结构和视网膜电生理功能，并进行视网膜组织学评估。
与(+)-PTZ 相似，SA4503 和 PRE084 提高了细胞活力，减轻了氧化应激，增加了 Nrf2、Nqo1 和 Cat 的表达。尽管 (+)-PTZ 治疗 rd10 小鼠可提高视力、增加外视网膜厚度并改善光刺激 a-和 b-波反应，但 SA4503 或 PRE084 治疗则没有。SA4503 和 PRE084 治疗 rd10 小鼠的光感受器细胞核/100µm 视网膜长度（约 11/100）与未治疗 rd10 小鼠无显著差异，而(+)-PTZ 治疗的小鼠则有更多的细胞核（约 22/100µm）。
当在体外进行 SA4503、PRE084 或(+)-PTZ 时，细胞存活和基因调节实验产生了相似的结果，但是在严重的 rd10 视网膜病变模型中，SA4503 和 PRE084 均不能提供与(+)-PTZ 相当的体内保护作用。尽管这三种化合物都具有激活西格玛 1 受体的潜力，但这三种配体的视网膜神经保护特性有显著差异。
