Valproic Acid Decreases Retinal Thickness in AMD Patients and Increases Fluid Absorption (JV) Across Human Retinal Pigment Epithelium in vitro

Abstract

Purpose: : Histone deacetylase inhibitors (HDIs) are therapeutic in mouse models of CNS disease. We measured the effects of HDIs such as valproic acid (VPA) on central macular thickness in AMD patients. We also measured the in vitro effects of VPA, its structural analog valpromide (VPD), and another HDI, 4-phenylbutyrate (PBA), on RPE J_v, transepithelial potential (TEP), and total RPE tissue resistance (TER).

Methods: : Three patients with exudative AMD refractory to ranibizumab and bevacizumab used 250 mg of VPA twice daily for 12 weeks. Central macular thickness by optical coherence topography was measured on the day prior to beginning VPA treatment and at 6 and 12 weeks following initiation of treatment. J_V, TEP, and TER were measured in primary cultures of human fetal RPE mounted as confluent monolayers using a capacitance probe and standard electrical recording techniques.

Results: : After 6 weeks of VPA use, the central macular thickness decreased from 532 to 403 µm; Δ=129±90. After 12 weeks, the central macular thickness further decreased to 297 µm; Δ=235±99 µm (p=0.05). In confluent monolayers of hfRPE, VPA (100, 250, 500 µM) increased J_V (retina to choroid) from 9.8±2.4 to 13.4±2.6 µl·cm^-2·hr^-1 (n=9; p=0.02). Baseline TEP and R_T were 5.2±2.7 mV and 389±66 Ω•cm², respectively, and not significantly altered by VPA. PBA was without significant effect on J_V or TEP, but decreased TER by 9±2 % (n=4;p=0.04). VPD (100, 400, 800 µM) had no significant effect on J_V, TEP or TER (n=5).

Conclusions: : Reduced central macular thickness was observed in 3 AMD patients treated with VPA (oral administration appears to be safe). In vitro, VPA increased J_V by 3.6 µl·cm^-2·hr^-1, and this increased absorption would remove a clinically significant amount of fluid, ≈0.7 ml daily, if it occurred across the back of the eye (≈8 cm²). We speculate that the apparent therapeutic effect of oral VPA may in part be mediated by its actions on the RPE fluid transport engine.

Keywords: age-related macular degeneration • retinal pigment epithelium