Departamento de Óptica, Farmacología y Anatomía, Universidad de Alicante, Ctra. San Vicente del Raspeig s/n, 03690 San Vicente del Raspeig, Spain.
Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, Ctra. San Vicente del Raspeig s/n, 03690 San Vicente del Raspeig, Spain.
Biomed Pharmacother. 2022 May;149:112911. doi: 10.1016/j.biopha.2022.112911. Epub 2022 Apr 4.
This review focuses on retina degeneration occurring during glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP), and on the potential therapeutic use of triads of repositioned medicines, addressed to distinct but complementary targets, to prevent, delay or stop retina cell death. Although myriad pathogenic mechanisms have been implicated in these disorders, common signaling pathways leading to apoptotic cell death to all of them, and to all neurodegenerative diseases are (i) calcium dyshomeostasis/excitotoxicity; (ii) oxidative stress/mitochondrial dysfunction, and (iii) neuroinflammation/P2X7 receptor activation. From a therapeutic point of view, it is relevant to consider the multitarget approach based on the use of combined medicines acting on complementary pathogenic mechanisms that has been highly successful in the treatment of chronic diseases such as cancer, AIDS, pain, hypertension, Parkinson's disease, cardiac failure, depression, or the epilepsies as the basic mechanisms of cell death do not differ between the different CNS degenerative diseases. We suggest the multi-target therapy approach could be more effective compared with single-drug treatments. Used at doses lower than standard, these triads may also be safer and more efficient. After the establishment of a proof-of-concept in animal models of retinal degeneration, potential successful preclinical trials of such combinations may eventually drive to test this concept in clinical trials in patients, first to evaluate the safety and efficacy of the drug combinations in humans and then their therapeutic advantages, if any, seeking the prevention and/or the delay of retina degeneration and blindness.
这篇综述重点介绍了青光眼、年龄相关性黄斑变性（AMD）、糖尿病性视网膜病变（DR）和色素性视网膜炎（RP）中发生的视网膜变性，以及针对不同但互补的靶点重新定位的三联药物在治疗中的潜在用途，以预防、延缓或阻止视网膜细胞死亡。尽管有无数的致病机制与这些疾病有关，但导致所有这些疾病和所有神经退行性疾病的共同信号通路是（i）钙稳态失衡/兴奋性毒性；（ii）氧化应激/线粒体功能障碍；以及（iii）神经炎症/P2X7 受体激活。从治疗的角度来看，考虑基于联合用药的多靶点方法是相关的，这些联合用药作用于互补的致病机制，在治疗癌症、艾滋病、疼痛、高血压、帕金森病、心力衰竭、抑郁症或癫痫等慢性疾病方面取得了巨大成功，因为细胞死亡的基本机制在不同的中枢神经系统退行性疾病之间没有差异。我们建议，与单一药物治疗相比，多靶点治疗方法可能更有效。以低于标准的剂量使用这些三联药物，也可能更安全、更有效。在动物视网膜变性模型中确立了概念验证后，这些组合的潜在成功临床前试验最终可能会促使在患者中进行临床试验来检验这一概念，首先评估药物组合在人体中的安全性和有效性，然后评估其治疗优势（如果有），以寻求预防和/或延缓视网膜变性和失明。
