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Huiyi Chen, Ajay Sharma, Marcos Reyes, Nishant R Sinha, Saad Siddiqui, Rajiv R Mohan; Suberoylanilide Hydroxamic Acid (SAHA) Inhibits Excess Fibrosis in Glaucoma Filtration Surgery: the Animal Study and Molecular Mechanisms. Invest. Ophthalmol. Vis. Sci. 2014;55(13):3205.
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Glaucoma filtration surgery (GFS) is routinely used to treat glaucoma. The postoperative subconjunctival fibrosis is a major cause of bleb failure and reduces the benefits of GFS. Mitomycin C (MMC) is currently used in clinical practice to treat this. However, MMC is cytotoxic and causes many complications. Our earlier studies found SAHA, a histone deacetylase inhibitor (HDACi), inhibits corneal fibrosis potently by modulating gene expression. SAHA is a FDA-approved drug for cancer. This study tested the anti-fibrotic efficacy and safety of intraoperative SAHA treatment during GFS.
New Zealand White rabbits were subjected to sclerotomy surgery. One group received subconjunctival injection of 50uM SAHA (0.2ml) and the other received balanced saline solution (BSS) 30 minutes before the GFS. The intraocular pressure (IOP), bleb appearance and vascularity, and slit lamp biomicroscopy were performed on day-0, 3, 7, and 14 after the surgery. On postoperative day 14, rabbits were sacrificed and the bleb tissues were collected and frozen. The tissue fibrosis was evaluated with H&E, Masson trichrome (MT), α-smooth muscle actin (SMA), and F-actin staining. The change in RNA expression in +/- of SAHA in bleb tissues or conjunctival fibroblasts in vitro was quantified by real-time RT-PCR.
SAHA-treated eyes showed significantly higher bleb length (p<0.001) and area (p<0.01), lower IOP, and decreased vascularity compared to BSS-treated eyes. Further, SAHA treatment significantly decreased fibrous conjunctival tissues (p<0.01), collagen deposit (p<0.05), f-actin (p<0.01), and SMA (p<0.001) at the sclerotomy site compared to negative controls. No apparent severe clinical symptoms of toxicity in eyes receiving SAHA were observed. The RT-PCR analysis of samples is underway.
HDAC inhibition is an attractive pharmacological target to modulate GFS wound healing. Adjunct SAHA treatment in GFS surgery could be clinically used to enhance GFS benefits without major side effects.
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