补体因子 B 的抑制或缺失不足以防止小鼠青光眼模型中的神经变性。

IF 1.9 4区 医学 Q2 OPHTHALMOLOGY Journal of Ocular Pharmacology and Therapeutics Pub Date : 2024-10-01 Epub Date: 2024-07-08 DOI:10.1089/jop.2024.0046
Katie Dolan, Sha-Mei Liao, Maura Crowley, Chuanxi Xiang, Christopher M Adams, Ann Brown, Nhi Vo, Amy Chen, Omar Delgado, Natasha Buchanan, Chenying Guo, Ganesh Prasanna
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引用次数: 0

摘要

目的:经典补体途径的激活被认为是导致青光眼发生和发展的原因之一。替代性补体或扩增途径在青光眼中的作用尚不十分清楚。我们评估了有或没有青光眼的死后人类眼组织中补体因子 B(FB)的表达情况,以及在光聚合透明质酸缩水甘油甲基丙烯酸酯(HAGM)诱导的小鼠眼压增高性青光眼模型中抑制和缺失 FB 的效果。方法:用 RNAscope 和 TaqMan 评估人眼中的 CFB mRNA。在 C57BL6/J 小鼠身上建立 HAGM 模型。用口服 FB 抑制剂和 Cfb-/- 小鼠评估 FB 对 HAGM 模型的影响。通过 TaqMan 和 Western 印迹分别评估了小鼠眼中的补体 mRNA 和蛋白质。结果人青光眼黄斑神经视网膜和视神经头的 CFB mRNA 上调。Cfb mRNA在HAGM模型中也上调。口服 FB 抑制剂 ED-79-GX17 在野生型小鼠眼内压(IOP)诱导后,以每天 200 毫克/千克的剂量连续服用 3 天,可抑制眼组织中的补体,并显著抑制全身补体水平。每天服用 ED-79-GX17 30 天或 Cfb 缺失也无法防止小鼠眼压诱导 30 天后视网膜神经节细胞或轴突丢失。结论在HAGM小鼠青光眼模型中,尽管Cfb表达上调并激活了替代途径,但替代补体成分FB可能不会对RGC的丧失起到实质性作用。这些发现与人类青光眼的相关性仍有待确定。
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Complement Factor B Inhibition or Deletion Is Not Sufficient to Prevent Neurodegeneration in a Murine Model of Glaucoma.

Purpose: Activation of the classical complement pathway is thought to contribute to the development and progression of glaucoma. The role of alternative complement or amplification pathways in glaucoma is not well understood. We evaluated complement factor B (FB) expression in postmortem human ocular tissues with or without glaucoma and the effect of FB inhibition and deletion in a mouse ocular hypertensive model of glaucoma induced by photopolymerized hyaluronic acid glycidyl methacrylate (HAGM). Methods: Human CFB mRNA in human eyes was assessed by RNAscope and TaqMan. HAGM model was performed on C57BL6/J mice. The effect of FB in HAGM model was evaluated with an oral FB inhibitor and Cfb-/- mice. Complement mRNA and proteins in mouse eyes were assessed by TaqMan and western blot, respectively. Results: CFB mRNA in human glaucomatous macular neural retina and optic nerve head was upregulated. Cfb mRNA is also upregulated in the HAGM model. Oral FB inhibitor, ED-79-GX17, dosed daily at 200 mg/kg for 3 days after intraocular pressure (IOP) induction in wild-type mice showed complement inhibition in ocular tissues and significantly inhibited systemic complement levels. Daily dosing of ED-79-GX17 for 30 days or Cfb deletion was also unable to prevent retinal ganglion cell or axon loss 30 days after IOP induction in mice. Conclusion: The alternative complement component FB may not substantially contribute to RGC loss in the HAGM mouse glaucoma model despite upregulation of Cfb expression and activation of the alternative pathway. The relevance of these findings to human glaucoma remains to be determined.

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来源期刊
CiteScore
4.60
自引率
4.30%
发文量
72
审稿时长
1 months
期刊介绍: Journal of Ocular Pharmacology and Therapeutics is the only peer-reviewed journal that combines the fields of ophthalmology and pharmacology to enable optimal treatment and prevention of ocular diseases and disorders. The Journal delivers the latest discoveries in the pharmacokinetics and pharmacodynamics of therapeutics for the treatment of ophthalmic disorders. Journal of Ocular Pharmacology and Therapeutics coverage includes: Glaucoma Cataracts Retinal degeneration Ocular infection, trauma, and toxicology Ocular drug delivery and biotransformation Ocular pharmacotherapy/clinical trials Ocular inflammatory and immune disorders Gene and cell-based therapies Ocular metabolic disorders Ocular ischemia and blood flow Proliferative disorders of the eye Eyes on Drug Discovery - written by Gary D. Novack, PhD, featuring the latest updates on drug and device pipeline developments as well as policy/regulatory changes by the FDA.
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