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
{"title":"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。","authors":"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","doi":"10.1089/jop.2024.0046","DOIUrl":null,"url":null,"abstract":"<p><p><b><i>Purpose:</i></b> 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). <b><i>Methods:</i></b> Human <i>CFB</i> 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 <i>Cfb</i><sup>-/-</sup> mice. Complement mRNA and proteins in mouse eyes were assessed by TaqMan and western blot, respectively. <b><i>Results:</i></b> <i>CFB</i> mRNA in human glaucomatous macular neural retina and optic nerve head was upregulated. <i>Cfb</i> 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 <i>Cfb</i> deletion was also unable to prevent retinal ganglion cell or axon loss 30 days after IOP induction in mice. <b><i>Conclusion:</i></b> The alternative complement component FB may not substantially contribute to RGC loss in the HAGM mouse glaucoma model despite upregulation of <i>Cfb</i> expression and activation of the alternative pathway. The relevance of these findings to human glaucoma remains to be determined.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":1.9000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Complement Factor B Inhibition or Deletion Is Not Sufficient to Prevent Neurodegeneration in a Murine Model of Glaucoma.\",\"authors\":\"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\",\"doi\":\"10.1089/jop.2024.0046\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b><i>Purpose:</i></b> 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). <b><i>Methods:</i></b> Human <i>CFB</i> 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 <i>Cfb</i><sup>-/-</sup> mice. Complement mRNA and proteins in mouse eyes were assessed by TaqMan and western blot, respectively. <b><i>Results:</i></b> <i>CFB</i> mRNA in human glaucomatous macular neural retina and optic nerve head was upregulated. <i>Cfb</i> 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 <i>Cfb</i> deletion was also unable to prevent retinal ganglion cell or axon loss 30 days after IOP induction in mice. <b><i>Conclusion:</i></b> The alternative complement component FB may not substantially contribute to RGC loss in the HAGM mouse glaucoma model despite upregulation of <i>Cfb</i> expression and activation of the alternative pathway. The relevance of these findings to human glaucoma remains to be determined.</p>\",\"PeriodicalId\":16689,\"journal\":{\"name\":\"Journal of Ocular Pharmacology and Therapeutics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2024-10-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Ocular Pharmacology and Therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1089/jop.2024.0046\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/8 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"OPHTHALMOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Ocular Pharmacology and Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1089/jop.2024.0046","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/8 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}
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.
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.