School of Pharmacy, University College Cork, Cork, Ireland.
Department of Pharmaceutical Technology, Tanta University, Tanta, Egypt.
Br J Ophthalmol. 2022 Sep;106(9):1187-1195. doi: 10.1136/bjophthalmol-2021-319115. Epub 2021 May 7.
Neovascular ocular diseases (such as age-related macular degeneration, diabetic retinopathy and retinal vein occlusion) are characterised by common pathological processes that contribute to disease progression. These include angiogenesis, oedema, inflammation, cell death and fibrosis. Currently available therapies target the effects of vascular endothelial growth factor (VEGF), the main mediator of pathological angiogenesis. Unfortunately, VEGF blockers are expensive biological therapeutics that necessitate frequent intravitreal administration and are associated with multiple adverse effects. Thus, alternative treatment options associated with fewer side effects are required for disease management. This review introduces sphingosine 1-phosphate (S1P) as a potential pharmacological target for the treatment of neovascular ocular pathologies. S1P is a sphingolipid mediator that controls cellular growth, differentiation, survival and death. S1P actions are mediated by five G protein-coupled receptors (S1P receptors) which are abundantly expressed in all retinal and subretinal structures. The action of S1P on S1P receptors can reduce angiogenesis, increase endothelium integrity, reduce photoreceptor apoptosis and protect the retina against neurodegeneration. Conversely, S1P receptor signalling can increase neovascularisation, disrupt endothelial junctions, stimulate VEGF release, and induce retinal cell apoptosis and degeneration of neural retina. The aim of this review is to thoroughly discuss the role of S1P and its different receptor subtypes in angiogenesis, inflammation, apoptosis and fibrosis in order to determine which of these S1P-mediated processes may be targeted therapeutically.
新生血管性眼病（如年龄相关性黄斑变性、糖尿病性视网膜病变和视网膜静脉阻塞）的特征是具有共同的病理过程，这些过程导致疾病进展。这些过程包括血管生成、水肿、炎症、细胞死亡和纤维化。目前可用的治疗方法针对血管内皮生长因子（VEGF）的作用，VEGF 是病理性血管生成的主要介质。不幸的是，VEGF 阻滞剂是昂贵的生物治疗药物，需要频繁的玻璃体内给药，并且与多种不良反应相关。因此，需要有与较少副作用相关的替代治疗方案来进行疾病管理。这篇综述介绍了鞘氨醇 1-磷酸（S1P）作为治疗新生血管性眼病的潜在药理靶点。S1P 是一种控制细胞生长、分化、存活和死亡的鞘脂介质。S1P 通过五个 G 蛋白偶联受体（S1P 受体）发挥作用，这些受体在所有视网膜和视网膜下结构中都大量表达。S1P 对 S1P 受体的作用可以减少血管生成，增加内皮完整性，减少光感受器细胞凋亡，并保护视网膜免受神经退行性变。相反，S1P 受体信号可以增加新生血管形成，破坏内皮连接，刺激 VEGF 释放，并诱导视网膜细胞凋亡和神经视网膜变性。本综述的目的是全面讨论 S1P 及其不同受体亚型在血管生成、炎症、细胞凋亡和纤维化中的作用，以确定哪些 S1P 介导的过程可以作为治疗靶点。
