Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham (UAB), Birmingham, AL.
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK.
Mol Vis. 2022 Oct 16;28:378-393. eCollection 2022.
Sulforaphane (SFN) is an isothiocyanate derived from cruciferous vegetables that has therapeutic efficacy in numerous animal models of human disease, including mouse models of retinal degeneration. However, despite dozens of clinical trials, the compound remains to be tested as a clinical treatment for ocular disease. Numerous cellular activities of SFN have been identified, including the activation of Nrf2, a transcription factor that induces a battery of target gene products to neutralize oxidative and xenobiotic stresses. As Nrf2 expression and function reportedly decrease with aging, we tested whether the loss of the transcription factor limits the therapeutic efficacy of SFN against retinal degeneration.
Six- to 8-month-old wild-type and Nrf2 knockout mice were treated with SFN beginning 1 month after ribozyme-mediated knockdown of superoxide dismutase 2 (SOD2) mRNA in the RPE. The impacts of MnSOD (the protein product of SOD2) knockdown and the efficacy of SFN were evaluated using a combination of electroretinography (ERG), spectral domain optical coherence tomography (SD-OCT), and postmortem histology.
SFN restored the ERG photopic b-wave suppressed by MnSOD loss in wild-type mice, but not in the Nrf2 knockout mice. In contrast, ERG scotopic a- and b-wave loss was not restored for either genotype. SFN significantly improved retinal thickness in the Nrf2 knockout mice with MnSOD knockdown, but this was not observed in the wild-type mice. In both genotypes, SFN treatment reduced morphological markers of RPE atrophy and degeneration, although these improvements did not correlate proportionally with functional recovery.
These findings highlight the capacity of SFN to preserve cone function, as well as the potential challenges of using the compound as a standalone treatment for age-related retinal degeneration under conditions associated with reduced Nrf2 function.
萝卜硫素（SFN）是一种源自十字花科蔬菜的异硫氰酸盐，在许多人类疾病的动物模型中具有治疗功效，包括老鼠视网膜变性模型。然而，尽管进行了数十项临床试验，该化合物仍未被测试作为眼部疾病的临床治疗方法。SFN 的许多细胞活性已被确定，包括 Nrf2 的激活，Nrf2 是一种转录因子，可诱导一系列靶基因产物来中和氧化和外来应激。由于 Nrf2 的表达和功能据称随着年龄的增长而降低，我们测试了转录因子的缺失是否限制了 SFN 对视网膜变性的治疗效果。
6 至 8 月龄的野生型和 Nrf2 敲除小鼠在 RPE 中用核糖核酸酶介导的超氧化物歧化酶 2（SOD2）mRNA 敲低后 1 个月开始用 SFN 治疗。使用视网膜电图（ERG）、光谱域光相干断层扫描（SD-OCT）和死后组织学的组合评估 MnSOD（SOD2 的蛋白产物）敲低的影响和 SFN 的疗效。
SFN 恢复了野生型小鼠中 MnSOD 缺失抑制的 ERG 光诱 b 波，但在 Nrf2 敲除小鼠中则没有。相比之下，ERG 暗诱 a 波和 b 波的丢失在两种基因型中都没有恢复。SFN 显著改善了 MnSOD 敲低的 Nrf2 敲除小鼠的视网膜厚度，但在野生型小鼠中则没有观察到。在两种基因型中，SFN 治疗均减少了 RPE 萎缩和变性的形态学标志物，尽管这些改善与功能恢复不成比例。
这些发现强调了 SFN 保留视锥细胞功能的能力，以及在与 Nrf2 功能降低相关的条件下，将该化合物作为单独治疗年龄相关性视网膜变性的潜在挑战。
