Effects of Valproic Acid and Mitomycin C Combination Therapy in a Rabbit Model of Minimally Invasive Glaucoma Surgery

Abstract

Purpose This study aimed to compare the effectiveness of combination therapy consisting of low-dose mitomycin C (MMC) and valproic acid (VPA) against high-dose MMC for improving the scar phenotype in minimally invasive glaucoma surgery (MIGS). Methods A rabbit model of MIGS incorporating the PreserFlo MicroShunt was treated with high (0.4 mg/mL) or low (0.1 mg/mL) doses of MMC or with combination therapy consisting of low-dose (0.1 mg/mL) MMC and VPA. Operated eyes were examined by live ocular imaging, histochemical evaluation, multiphoton quantitation of collagen characteristics, and molecular analyses. Results Although high-dose MMC obliterated the vasculature, combination therapy vastly improved the postoperative tissue morphology by maintaining the vasculature without increased vascularization. Combination therapy also altered collagen morphology and reduced encapsulation of the MicroShunt distal end, which remained at risk with MMC treatment alone. Multiphoton quantitation indicated that the combination therapy significantly reduced collagen density and fiber dimensions compared with monotherapy. At the molecular level, combination therapy significantly reduced Vegfa , Vegfc , and Vegfd expression and inhibited Col1a1 upregulation from baseline levels, all of which low-dose MMC alone was unable to achieve. Notably, COL1A1 protein levels appeared more consistently suppressed by combination therapy compared with high-dose MMC alone. Conclusions Compared with high-dose MMC, combination therapy was less toxic by sparing the vasculature and potentially more effective in reducing scarring via the regulation of collagen content and organization. Translational Relevance VPA may be combined with low-dose MMC to replace high-dose MMC to deliver safe and effective anti-scarring outcomes.

Wound Modulations in Glaucoma Surgery: A Systematic Review

“…Additionally, VPA was found to suppress collagen and fibronectin gene expression, while enhancing the expression of factors disrupting TGF-β pathways. Another study comparing the concomitant usage of VPA and MMC with varying doses of MMC in a rabbit model of the PreserFlo ® MicroShunt found that the combination therapy was less cytotoxic when compared to MMC alone [70]. Moreover, the combination decreased VEGF and collagen gene expression more than MMC alone was able to.…”

Novel Therapies for the Prevention of Fibrosis in Glaucoma Filtration Surgery

“…This progression is due to the MMC-induced apoptosis of conjunctival connective fibroblasts [ 120 ]. The toxic effects of MMC may be mitigated by combining a lower dosage of MMC with valproic acid, which has been demonstrated in a rabbit model [ 121 , 122 ]. There is no definite clinical recommendation for post-operative 5-FU as opposed to MMC.…”

Scar formation in the presence of mitomycin C and the anti-fibrotic antibody in a rabbit model of glaucoma microsurgery: A pilot study

“…Although MMC reduces scar formation, bleb failure is a common outcome despite its use [ 5 ]. Using MMC also carries the risk of significant side effects, including conjunctival epithelium breakdown, hypotony, and endophthalmitis [ [6] , [7] , [8] , [9] ]. Consequently, effective and safe adjuncts to glaucoma filtering surgery that prevent the excessive deposition of collagen-rich scar tissue would potentially reduce or inhibit channel blockage, thus reducing the need for repeat surgeries.…”