Department of Pharmacology and Neuroscience and the North Texas Eye Research Institute, IREB-535, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.
Mol Neurodegener. 2020 Aug 27;15(1):48. doi: 10.1186/s13024-020-00400-9.
Glaucoma is a leading neurodegenerative disease affecting over 70 million individuals worldwide. Early pathological events of axonal degeneration and retinopathy in response to elevated intraocular pressure (IOP) are limited and not well-defined due to the lack of appropriate animal models that faithfully replicate all the phenotypes of primary open angle glaucoma (POAG), the most common form of glaucoma. Glucocorticoid (GC)-induced ocular hypertension (OHT) and its associated iatrogenic open-angle glaucoma share many features with POAG. Here, we characterized a novel mouse model of GC-induced OHT for glaucomatous neurodegeneration and further explored early pathological events of axonal degeneration in response to elevated IOP.
C57BL/6 J mice were periocularly injected with either vehicle or the potent GC, dexamethasone 21-acetate (Dex) once a week for 10 weeks. Glaucoma phenotypes including IOP, outflow facility, structural and functional loss of retinal ganglion cells (RGCs), optic nerve (ON) degeneration, gliosis, and anterograde axonal transport deficits were examined at various stages of OHT.
Prolonged treatment with Dex leads to glaucoma in mice similar to POAG patients including IOP elevation due to reduced outflow facility and dysfunction of trabecular meshwork, progressive ON degeneration and structural and functional loss of RGCs. Lowering of IOP rescued Dex-induced ON degeneration and RGC loss, suggesting that glaucomatous neurodegeneration is IOP dependent. Also, Dex-induced neurodegeneration was associated with activation of astrocytes, axonal transport deficits, ON demyelination, mitochondrial accumulation and immune cell infiltration in the optic nerve head (ONH) region. Our studies further show that ON degeneration precedes structural and functional loss of RGCs in Dex-treated mice. Axonal damage and transport deficits initiate at the ONH and progress toward the distal end of ON and target regions in the brain (i.e. superior colliculus). Most of anterograde transport was preserved during initial stages of axonal degeneration (30% loss) and complete transport deficits were only observed at the ONH during later stages of severe axonal degeneration (50% loss).
These findings indicate that ON degeneration and transport deficits at the ONH precede RGC structural and functional loss and provide a new potential therapeutic window for rescuing neuronal loss and restoring health of damaged axons in glaucoma.
青光眼是一种主要的神经退行性疾病，影响着全球超过 7000 万人。由于缺乏能够真实复制原发性开角型青光眼（POAG）所有表型的合适动物模型，导致轴突变性和视网膜病变等早期病理事件受到限制，且尚未得到明确界定。POAG 是最常见的青光眼类型。糖皮质激素（GC）诱导的眼压升高（OHT）及其相关的医源性开角型青光眼与 POAG 有许多共同特征。在这里，我们描述了一种新的 GC 诱导的 OHT 小鼠模型，用于研究青光眼性神经退行性变，并进一步探讨了眼压升高时轴突变性的早期病理事件。
每周一次向 C57BL/6J 小鼠眼周注射载体或强效 GC 地塞米松 21-醋酸酯（Dex），共 10 周。在 OHT 的不同阶段，检查眼压（IOP）、流出物通畅性、视网膜神经节细胞（RGC）的结构和功能丧失、视神经（ON）变性、神经胶质增生和顺行轴突运输缺陷等青光眼表型。
Dex 的长期治疗会导致小鼠发生类似于 POAG 患者的青光眼，包括由于流出物通畅性降低和小梁网功能障碍导致的 IOP 升高、进行性 ON 变性以及 RGC 的结构和功能丧失。降低 IOP 可挽救 Dex 诱导的 ON 变性和 RGC 丧失，表明青光眼性神经退行性变与 IOP 有关。此外，Dex 诱导的神经退行性变与星形胶质细胞的激活、轴突运输缺陷、ON 脱髓鞘、线粒体积累和视神经头部（ONH）区域的免疫细胞浸润有关。我们的研究进一步表明，在 Dex 处理的小鼠中，ON 变性先于 RGC 的结构和功能丧失。轴突损伤和运输缺陷始于 ONH，并向 ON 的远端和大脑中的靶区（即上丘）进展。在轴突变性的初始阶段（丧失 30%），大部分顺行运输仍然保留，只有在严重轴突变性的后期阶段（丧失 50%）才会观察到 ONH 处的完全运输缺陷。
这些发现表明，ONH 处的 ON 变性和运输缺陷先于 RGC 的结构和功能丧失，并为挽救神经元丧失和恢复青光眼受损轴突的健康提供了一个新的潜在治疗窗口。
