Glaucoma is a multifactorial neurodegenerative disease associated with retinal ganglion cells (RGC) loss. Increasing reports of similarities in glaucoma and other neurodegenerative conditions have led to speculation that therapies for brain neurodegenerative disorders may also have potential as glaucoma therapies. Memantine is an N‐methyl‐d‐aspartate (NMDA) antagonist approved for Alzheimer's disease treatment. Glutamate‐induced excitotoxicity is implicated in glaucoma and NMDA receptor antagonism is advocated as a potential strategy for RGC preservation. This study describes the development of a topical formulation of memantine‐loaded PLGA‐PEG nanoparticles (MEM‐NP) and investigates the efficacy of this formulation using a well‐established glaucoma model. MEM‐NPs <200 nm in diameter and incorporating 4 mg mL⁻¹ of memantine were prepared with 0.35 mg mL⁻¹ localized to the aqueous interior. In vitro assessment indicated sustained release from MEM‐NPs and ex vivo ocular permeation studies demonstrated enhanced delivery. MEM‐NPs were additionally found to be well tolerated in vitro (human retinoblastoma cells) and in vivo (Draize test). Finally, when applied topically in a rodent model of ocular hypertension for three weeks, MEM‐NP eye drops were found to significantly (p < 0.0001) reduce RGC loss. These results suggest that topical MEM‐NP is safe, well tolerated, and, most promisingly, neuroprotective in an experimental glaucoma model.

中文翻译：

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美金刚胺负载的聚乙二醇化可生物降解纳米粒子治疗青光眼

青光眼是与视网膜神经节细胞（RGC）丢失相关的多因素神经退行性疾病。关于青光眼和其他神经退行性疾病的相似性的报道不断增加，导致人们猜测脑神经退行性疾病的疗法也可能具有青光眼疗法的潜力。美金刚是Ñ甲基d天冬氨酸（NMDA）拮抗剂已批准用于阿尔茨海默氏病的治疗。谷氨酸引起的兴奋性毒性与青光眼有关，而NMDA受体拮抗作用被认为是RGC保存的潜在策略。这项研究描述了美金刚加载的PLGA-PEG纳米颗粒（MEM-NP）局部制剂的开发，并使用成熟的青光眼模型研究了该制剂的功效。制备直径小于200 nm并掺入4 mg mL ^-1美金刚的MEM‐NP和0.35 mg mL ^-1定位于水性内部。体外评估表明从MEM-NPs持续释放，离体眼部渗透研究表明分娩增强。还发现MEM-NP在体外（人视网膜母细胞瘤细胞）和体内（Draize试验）均具有良好的耐受性。最后，当在高眼啮齿动物模型中局部应用三周时，发现MEM-NP滴眼液可显着（p <0.0001）减少RGC损失。这些结果表明，在实验性青光眼模型中，局部MEM-NP是安全的，耐受性良好且最有希望的神经保护作用。