Decorin Reduces Intraocular Pressure and Retinal Ganglion Cell Loss in Rodents Through Fibrolysis of the Scarred Trabecular Meshwork.

Abstract

PURPOSE:

To investigate whether Decorin, a matrikine that regulates extracellular matrix (ECM) deposition, can reverse established trabecular meshwork (TM) fibrosis, lower IOP, and reduce progressive retinal ganglion cell (RGC) death in a novel rodent model of TM fibrosis.

METHODS:

Adult rats had intracameral (IC) injections of human recombinant (hr) TGF-β over 30 days (30 d; to induce TM fibrosis, raise IOP, and initiate RGC death by 17 d) or PBS (controls) and visually evoked potentials (VEP) were measured at 30 d to evaluate resultant visual pathway dysfunction. In some animals TGF-β injections were stopped at 17 d when TM fibrosis and IOP were consistently raised and either hrDecorin or PBS IC injections were administered between 21 d and 30 d. Intraocular pressure was measured biweekly and eyes were processed for immunohistochemical analysis of ECM deposition to assess TM fibrosis and levels of matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinases (TIMP) to assess fibrolysis. The effect of hrDecorin treatment on RGC survival was also assessed.

RESULTS:

Transforming growth factor-β injections caused sustained increases in ECM deposition in the TM and raised IOP by 17 d, responses that were associated with 42% RGC loss and a significant decrease in VEP amplitude measured at 30 d. Decorin treatment from 17 d reduced TGF-β-induced TM fibrosis, increased levels of MMP2 and MMP9 and lowered TIMP2 levels, and lowered IOP, preventing progressive RGC loss.

CONCLUSIONS:

Human recombinant Decorin reversed established TM fibrosis and lowered IOP, thereby rescuing RGC from progressive death. These data provide evidence for the candidacy of hrDecorin as a treatment for open-angle glaucoma.

• Authors: Lisa J Hill, Ben Mead, Richard J Blanch, Zubair Ahmed, Felicity De Cogan, Peter J Morgan-Warren, Shabbir Mohamed, Wendy Leadbeater, Robert A H Scott, Martin Berry, Ann Logan
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 56 Issue 6 Pg. 3743-57 (Jun 2015) ISSN: 1552-5783 [Electronic] United States
• PMID: 26066743 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Decorin

Topics

• Animals
• Cell Death (drug effects)
• Decorin (pharmacology, therapeutic use)
• Fibrosis (drug therapy)
• Intraocular Pressure (drug effects)
• Male
• Rats
• Rats, Sprague-Dawley
• Retinal Ganglion Cells (drug effects, pathology)
• Trabecular Meshwork (pathology)