Gavin Herbert Eye Institute and the Department of Ophthalmology, University of California-Irvine, Irvine, California, United States.
Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio, United States.
Invest Ophthalmol Vis Sci. 2019 Apr 1;60(5):1442-1453. doi: 10.1167/iovs.19-26560.
The purpose of this study was to test the extent of light damage in different models of night blindness and apply these paradigms in testing the therapeutic efficacy of combination therapy by drugs acting on the Gi, Gs, and Gq protein-coupled receptors.
Acute bright light exposure was used to test susceptibility to light damage in mice lacking the following crucial phototransduction proteins: rod transducin (GNAT1), cone transducin (GNAT2), visual arrestin 1 (ARR1), and rhodopsin kinase 1 (GRK1). Mice were intraperitoneally injected with either vehicle or drug combination consisting of metoprolol (β1-receptor antagonist), bromocriptine (dopamine family-2 receptor agonist) and tamsulosin (α1-receptor antagonist) before bright light exposure. Light damage was primarily assessed with optical coherence tomography and inspection of cone population in retinal whole mounts. Retinal inflammation was assessed in a subset of experiments using autofluorescence imaging by scanning laser ophthalmoscopy and by postmortem inspection of microglia and astrocyte activity.
The Gnat1-/- mice showed slightly increased susceptibility to rod light damage, whereas the Gnat2-/- mice were very resistant. The Arr1-/- and Grk1-/- mice were sensitive for both rod and cone light damage and showed robust retinal inflammation 7 days after bright light exposure. Pretreatment with metoprolol + bromocriptine + tamsulosin rescued the retina in all genetic backgrounds, starting at doses of 0.2 mg/kg metoprolol, 0.02 mg/kg bromocriptine, and 0.01 mg/kg tamsulosin in the Gnat1-/- mice. The therapeutic drug doses increased in parallel with light-damage severity.
Our results suggest that congenital stationary night blindness and Oguchi disease patients can be at an elevated risk of the toxic effects of bright light. Furthermore, systems pharmacology drug regimens that stimulate Gi signaling and attenuate Gs and Gq signaling present a promising disease-modifying therapy for photoreceptor degenerative diseases.
本研究旨在测试不同类型夜盲症模型中的光损伤程度，并应用这些范例测试作用于 Gi、Gs 和 Gq 蛋白偶联受体的药物联合治疗的疗效。
急性强光暴露用于测试缺乏以下关键光转导蛋白的小鼠对光损伤的易感性：视杆转导蛋白（GNAT1）、视锥转导蛋白（GNAT2）、视觉 arrestin 1（ARR1）和视紫红质激酶 1（GRK1）。在强光暴露前，小鼠经腹腔注射载体或由美托洛尔（β1 受体拮抗剂）、溴隐亭（多巴胺家族 2 受体激动剂）和坦索罗辛（α1 受体拮抗剂）组成的药物联合治疗。主要通过光学相干断层扫描和视网膜全层铺片检查视锥细胞群体来评估光损伤。在一部分实验中，使用扫描激光检眼镜的自发荧光成像和死后观察小胶质细胞和星形胶质细胞活性来评估视网膜炎症。
Gnat1-/- 小鼠对杆状光损伤的敏感性略有增加，而 Gnat2-/- 小鼠则非常耐受。Arr1-/- 和 Grk1-/- 小鼠对杆状和锥状光损伤均敏感，并且在强光暴露后 7 天显示出强烈的视网膜炎症。美托洛尔+溴隐亭+坦索罗辛预处理可挽救所有遗传背景下的视网膜，起始剂量为 Gnat1-/- 小鼠 0.2mg/kg 美托洛尔、0.02mg/kg 溴隐亭和 0.01mg/kg 坦索罗辛。治疗药物剂量与光损伤严重程度平行增加。
我们的结果表明，先天性静止性夜盲症和奥古希病患者可能面临强光毒性作用的风险增加。此外，刺激 Gi 信号并减弱 Gs 和 Gq 信号的系统药理学药物方案为光感受器退行性疾病提供了一种有前途的疾病修饰治疗方法。
