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Topical ocular sodium 4-phenylbutyrate rescues glaucoma in a myocilin mouse model of primary open-angle glaucoma
Journal article   Open access   Peer reviewed

Topical ocular sodium 4-phenylbutyrate rescues glaucoma in a myocilin mouse model of primary open-angle glaucoma

Gulab S Zode, Kevin E Bugge, Kabhilan Mohan, Sinisa D Grozdanic, Joseph C Peters, Demelza R Koehn, Michael G Anderson, Randy H Kardon, Edwin M Stone and Val C Sheffield
Investigative ophthalmology & visual science, Vol.53(3), pp.1557-1565
03/2012
DOI: 10.1167/iovs.11-8837
PMCID: PMC3339917
PMID: 22328638
url
https://doi.org/10.1167/iovs.11-8837View
Published (Version of record) Open Access

Abstract

Mutations in the myocilin gene (MYOC) are the most common known genetic cause of primary open-angle glaucoma (POAG). The purpose of this study was to determine whether topical ocular sodium 4-phenylbutyrate (PBA) treatment rescues glaucoma phenotypes in a mouse model of myocilin-associated glaucoma (Tg-MYOC(Y437H) mice). Tg-MYOC(Y437H) mice were treated with PBA eye drops (n = 10) or sterile PBS (n = 8) twice daily for 5 months. Long-term safety and effectiveness of topical PBA (0.2%) on glaucoma phenotypes were examined by measuring intraocular pressure (IOP) and pattern ERG (PERG), performing slit lamp evaluation of the anterior chamber, analyzing histologic sections of the anterior segment, and comparing myocilin levels in the aqueous humor and trabecular meshwork of Tg-MYOC(Y437H) mice. Tg-MYOC(Y437H) mice developed elevated IOP at 3 months of age when compared with wild-type (WT) littermates (n = 24; P < 0.0001). Topical PBA did not alter IOP in WT mice. However, it significantly reduced elevated IOP in Tg-MYOC(Y437H) mice to the level of WT mice. Topical PBA-treated Tg-MYOC(Y437H) mice also preserved PERG amplitudes compared with vehicle-treated Tg-MYOC(Y437H) mice. No structural abnormalities were observed in the anterior chamber of PBA-treated WT and Tg-MYOC(Y437H) mice. Analysis of the myocilin in the aqueous humor and TM revealed that PBA significantly improved the secretion of myocilin and reduced myocilin accumulation as well as endoplasmic reticulum (ER) stress in the TM of Tg-MYOC(Y437H) mice. Furthermore, topical PBA reduced IOP elevated by induction of ER stress via tunicamycin injections in WT mice. Topical ocular PBA reduces glaucomatous phenotypes in Tg-MYOC(Y437H) mice, most likely by reducing myocilin accumulation and ER stress in the TM. Topical ocular PBA could become a novel treatment for POAG patients with myocilin mutations.
 Immunohistochemistry Administration, Ophthalmic Intraocular Pressure - drug effects Ophthalmic Solutions - administration & dosage Humans Glycoproteins - metabolism Male Mice, Transgenic Glaucoma, Open-Angle - drug therapy Ocular Hypertension - drug therapy Aqueous Humor - metabolism Animals Eye Proteins - metabolism Tunicamycin - pharmacology Phenylbutyrates - administration & dosage Cytoskeletal Proteins - metabolism Female Glaucoma, Open-Angle - metabolism Anti-Bacterial Agents - pharmacology Eye - drug effects Mice Disease Models, Animal

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