Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida, USA.
Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.
WIREs Mech Dis. 2024 Jan-Feb;16(1):e1628. doi: 10.1002/wsbm.1628. Epub 2023 Sep 5.
Glaucoma is a heterogeneous group of progressive diseases that leads to irreversible blindness. Secondary glaucoma refers to glaucoma caused by a known underlying condition. Pseudoexfoliation and pigment dispersion syndromes are common causes of secondary glaucoma. Their respective deposits may obstruct the trabecular meshwork, leading to aqueous humor outflow resistance, ocular hypertension, and optic neuropathy. There are no disease-specific interventions available for either. Pseudoexfoliation syndrome is characterized by fibrillar deposits (pseudoexfoliative material) on anterior segment structures. Over a decade of multiomics analyses taken together with the current knowledge on pseudoexfoliative glaucoma warrant a re-think of mechanistic possibilities. We propose that the presence of nucleation centers (e.g., vitamin D binding protein), crosslinking enzymes (e.g., transglutaminase 2), aberrant extracellular matrix, flawed endocytosis, and abnormal aqueous-blood barrier contribute to the formation of proteolytically resistant pseudoexfoliative material. Pigment dispersion syndrome is characterized by abnormal iridolenticular contact that disrupts iris pigment epithelium and liberates melanin granules. Iris melanogenesis is aberrant in this condition. Cytotoxic melanogenesis intermediates leak out of melanosomes and cause iris melanocyte and pigment epithelium cell death. Targeting melanogenesis can likely decrease the risk of pigmentary glaucoma. Skin and melanoma research provides insights into potential therapeutics. We propose that specific prostanoid agonists and fenofibrates may reduce melanogenesis by inhibiting cholesterol internalization and de novo synthesis. Additionally, melatonin is a potent melanogenesis suppressor, antioxidant, and hypotensive agent, rendering it a valuable agent for pigmentary glaucoma. In pseudoexfoliative glaucoma, where environmental insults drive pseudoexfoliative material formation, melatonin's antioxidant and hypotensive properties may offer adjunct therapeutic benefits. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology.
青光眼是一组异质性的进行性疾病，可导致不可逆的失明。继发性青光眼是指由已知潜在疾病引起的青光眼。假性剥脱综合征和色素播散综合征是继发性青光眼的常见原因。它们各自的沉积物可能会阻塞小梁网，导致房水流出阻力增加、眼压升高和视神经病变。目前，这两种疾病都没有特定的治疗方法。假性剥脱综合征的特征是前节结构上有纤维状沉积物（假性剥脱物质）。十多年的多组学分析以及目前对假性剥脱性青光眼的认识，都需要重新考虑可能的发病机制。我们提出，成核中心（如维生素 D 结合蛋白）、交联酶（如转谷氨酰胺酶 2）、异常细胞外基质、有缺陷的内吞作用以及异常的血-房水屏障的存在，有助于形成具有蛋白水解抗性的假性剥脱物质。色素播散综合征的特征是虹膜-晶状体异常接触，破坏虹膜色素上皮并释放黑色素颗粒。在这种情况下，虹膜黑色素生成异常。细胞毒性黑色素生成中间产物从黑色素小体中漏出，导致虹膜黑色素细胞和色素上皮细胞死亡。针对黑色素生成可能会降低色素性青光眼的风险。皮肤和黑色素瘤研究为潜在的治疗方法提供了思路。我们提出，特定的前列腺素激动剂和非诺贝特可能通过抑制胆固醇内吞和从头合成来减少黑色素生成。此外，褪黑素是一种有效的黑色素生成抑制剂、抗氧化剂和降压剂，使其成为治疗色素性青光眼的有价值药物。在由环境刺激物驱动假性剥脱物质形成的假性剥脱性青光眼，褪黑素的抗氧化和降压特性可能提供辅助治疗益处。本文属于以下分类：神经疾病 > 分子和细胞生理学。
