Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
Department of Pharmacology, Cleveland Center for Membrane and Structural Biology, School of Medicine, Case Western Reserve University, Cleveland, Ohio
Mol Pharmacol. 2021 Jan;99(1):60-77. doi: 10.1124/molpharm.120.000072. Epub 2020 Nov 5.
Degeneration of photoreceptors caused by excessive illumination, inherited mutations, or aging is the principal pathology of blinding diseases. Pharmacological compounds that stabilize the visual receptor rhodopsin and modulate the cellular pathways triggering death of photoreceptors could avert this pathology. Interestingly, flavonoids can modulate the cellular processes, such as oxidative stress, inflammatory responses, and apoptosis, that are activated during retinal degeneration. As we found previously, flavonoids also bind directly to unliganded rod opsin, enhancing its folding, stability, and regeneration. In addition, flavonoids stimulate rhodopsin gene expression. Thus, we evaluated the effect of two main dietary flavonoids, quercetin and myricetin, in ATP-binding cassette subfamily A member 4 /retinol dehydrogenase 8 and wild-type BALB/c mice susceptible to light-induced photoreceptor degeneration. Using in vivo imaging, such as optical coherence tomography, scanning laser ophthalmoscopy, and histologic assessment of retinal morphology, we found that treatment with these flavonoids prior to light insult remarkably protected retina from deterioration and preserved its function. Using high-performance liquid chromatography-mass spectrometry analysis, we detected these flavonoids in the eye upon their intraperitoneal administration. The molecular events associated with the protective effect of quercetin and myricetin were related to the elevated expression of photoreceptor-specific proteins, rhodopsin and cone opsins, decreased expression of the specific inflammatory markers, and the shift of the equilibrium between cell death regulators BCL2-associated X protein (BAX) and B-cell lymphoma 2 toward an antiapoptotic profile. These results were confirmed in photoreceptor-derived 661W cells treated with either HO or all--retinal stressors implicated in the mechanism of retinal degeneration. Altogether, flavonoids could have significant prophylactic value for retinal degenerative diseases. SIGNIFICANCE STATEMENT: Flavonoids commonly present in food exhibit advantageous effects in blinding diseases. They bind to and stabilize unliganded rod opsin, which in excess accelerates degenerative processes in the retina. Additionally, flavonoids enhance the expression of the visual receptors, rod and cone opsins; inhibit the inflammatory reactions; and induce the expression of antiapoptotic markers in the retina, preventing the degeneration in vivo. Thus, flavonoids could have a prophylactic value for retinal degenerative diseases.
光照射过度、遗传突变或衰老导致的光感受器变性是致盲疾病的主要病理学特征。稳定视觉受体视紫红质并调节触发光感受器死亡的细胞途径的药物化合物可以防止这种病理学发生。有趣的是，类黄酮可以调节细胞过程，如氧化应激、炎症反应和细胞凋亡，这些过程在视网膜变性过程中被激活。正如我们之前发现的，类黄酮还可以直接与未配位的视杆蛋白结合，增强其折叠、稳定性和再生。此外，类黄酮还可以刺激视紫红质基因的表达。因此，我们评估了两种主要膳食类黄酮（槲皮素和杨梅素）在 ATP 结合盒亚家族 A 成员 4/视黄醇脱氢酶 8 和易发生光诱导光感受器变性的野生型 BALB/c 小鼠中的作用。通过活体成像，如光学相干断层扫描、扫描激光检眼镜和视网膜形态学的组织学评估，我们发现，在光损伤前用这些类黄酮进行治疗可显著保护视网膜免受恶化并维持其功能。通过高效液相色谱-质谱分析，我们在腹腔给予这些类黄酮后在眼睛中检测到了它们。槲皮素和杨梅素保护作用相关的分子事件与光感受器特异性蛋白视紫红质和视锥蛋白表达升高、特定炎症标志物表达降低以及细胞死亡调节剂 BCL2 相关 X 蛋白 (BAX) 和 B 细胞淋巴瘤 2 之间的平衡向抗凋亡谱转移有关。这些结果在接受 HO 或全视网膜应激物处理的光感受器衍生的 661W 细胞中得到了证实，这些应激物涉及视网膜变性的机制。总的来说，类黄酮对视神经退行性疾病可能具有重要的预防价值。意义：食物中常见的类黄酮具有有益的致盲疾病作用。它们与未配位的视杆蛋白结合并稳定视杆蛋白，过量的视杆蛋白会加速视网膜的退行性过程。此外，类黄酮还可以增强视紫红质和视锥蛋白的表达；抑制炎症反应；并在体内诱导抗凋亡标志物的表达，防止退行性变。因此，类黄酮对视神经退行性疾病可能具有预防价值。
