El-Darzi Nicole, Mast Natalia, Buchner David A, Saadane Aicha, Dailey Brian, Trichonas Georgios, Pikuleva Irina A
Departments of Ophthalmology and Visual Sciences, Cleveland, OH, United States.
Departments of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, United States.
Front Pharmacol. 2022 Jun 1;13:902254. doi: 10.3389/fphar.2022.902254. eCollection 2022.
A small dose of the anti-HIV drug efavirenz (EFV) was previously discovered to activate CYP46A1, a cholesterol-eliminating enzyme in the brain, and mitigate some of the manifestation of Alzheimer's disease in 5XFAD mice. Herein, we investigated the retina of these animals, which were found to have genetically determined retinal vascular lesions associated with deposits within the retinal pigment epithelium and subretinal space. We established that EFV treatment activated CYP46A1 in the retina, enhanced retinal cholesterol turnover, and diminished the lesion frequency >5-fold. In addition, the treatment mitigated fluorescein leakage from the aberrant blood vessels, deposit size, activation of retinal macrophages/microglia, and focal accumulations of amyloid β plaques, unesterified cholesterol, and Oil Red O-positive lipids. Studies of retinal transcriptomics and proteomics identified biological processes enriched with differentially expressed genes and proteins. We discuss the mechanisms of the beneficial EFV effects on the retinal phenotype of 5XFAD mice. As EFV is an FDA-approved drug, and we already tested the safety of small-dose EFV in patients with Alzheimer's disease, our data support further clinical investigation of this drug in subjects with retinal vascular lesions or neovascular age-related macular degeneration.
先前发现小剂量的抗艾滋病毒药物依法韦仑（EFV）可激活大脑中一种消除胆固醇的酶CYP46A1，并减轻5XFAD小鼠的一些阿尔茨海默病症状。在此，我们对这些动物的视网膜进行了研究，发现它们存在与视网膜色素上皮和视网膜下间隙内沉积物相关的遗传性视网膜血管病变。我们证实，EFV治疗可激活视网膜中的CYP46A1，增强视网膜胆固醇周转，并使病变频率降低5倍以上。此外，该治疗减轻了异常血管的荧光素渗漏、沉积物大小、视网膜巨噬细胞/小胶质细胞的激活以及淀粉样β斑块、未酯化胆固醇和油红O阳性脂质的局灶性积聚。视网膜转录组学和蛋白质组学研究确定了富含差异表达基因和蛋白质的生物学过程。我们讨论了EFV对5XFAD小鼠视网膜表型产生有益作用的机制。由于EFV是一种经美国食品药品监督管理局批准的药物，而且我们已经在阿尔茨海默病患者中测试了小剂量EFV的安全性，我们的数据支持对这种药物在患有视网膜血管病变或新生血管性年龄相关性黄斑变性的受试者中进行进一步的临床研究。
