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Masahiko Sugimoto, Mineo Kondo, Yoko Yoshida, Hitomi Tanimoto, Ryohei Nakamura, Hiroyoshi Hidaka; Therapeutic potential of a novel isoquinoline sulfonamide derivative with protein kinase inhibition function, H-1337, in wet AMD. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):150.
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© ARVO (1962-2015); The Authors (2016-present)
Exudative age-related macular degeneration (wet AMD) causes vision loss due to choroidal neovascularization (CNV). Here, we investigated the potential of a novel isoquinoline sulfonamide derivative, H-1337, and its main metabolite (H-1337M1), in ex vivo and an experimental CNV model as a potential therapeutic agent for wet AMD.
H-1337M1 was obtained from incubation of H-1337 with rabbit liver S9 fraction. ARPE-19 cells were pretreated with H-1337 or H-1337 M1 (1 μM for 25 h) and vascular endothelial growth factor (VEGF) concentration in culture supernatant was measured using ELISA. Cell migration was also assessed by wound healing assay. Cell proliferation was assessed by Cell Counting Kit-8 assay under same condition for human retinal microvascular endothelial cells (hRMECs) and human umbilical vascular endothelial cells (HUVEC). Effects of H-1337M1 on CNV were investigated in a rat laser-induced CNV model (6- to 10-week-old Brown Norway rats). After laser photocoagulation, H-1337M1 (intravitreal injections, 15 ng/eye, day 0 and day 7) was administered. Fluorescein angiography (FA) was performed after 2 wks and signal intensities in each laser spot were evaluated using Image J software.
Both H-1337 and H-1337M1 significantly reduced VEGF secretion by 28% and 38%, respectively (p < 0.01 compared with vehicle) and also inhibited cell proliferation of hRMECs (H-1337: with an IC50 of 4.3 μM, H-1337M1: with an IC50 of 4.4 μM) and HUVEC (H-1337: with an IC50 of 3.7 μM, H-1337M1: with an IC50 of 9.2 μM). Cell migration was significantly inhibited by H-1337 (at 30 μM, p < 0.001 compared with vehicle) and H-1337M1 (at 10 μM, p < 0.001 compared with vehicle). The intensities of FA leakage from CNV were also significantly reduced in H-1337M1-treated rats by 67% (p < 0.05 compared with vehicle).
H-1337 and H-1337M1 treatment has the potential to become a novel therapeutic strategy for wet AMD.
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