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Intravenous injection of l‐aspartic acid &bgr;‐hydroxamate attenuates choroidal neovascularization via anti‐VEGF and anti‐inflammation

Mengjuan Wu,Yimei Liu,He Zhang,Meiling Lian,Juan Chen,Haiyan Jiang,Ying Xu,G. Shan,Shengzhou or sheng-zhou wu

Published 2019 in Experimental Eye Research

ABSTRACT

Abstract Choroidal neovascularization (CNV) is a hallmark of exudative age‐related macular degeneration (exAMD) and a major cause of visual loss in AMD. Despite the widespread use of anti‐VEGF therapy, serious adverse effects arise from repeated intravitreal injection of anti‐VEGF antibodies, which warrant alternative strategy. We report herein that in a CNV murine model created by krypton red laser, intravenous injection of a serine racemase inhibitor, l‐Aspartic acid &bgr;‐hydroxamate (L‐ABH), significantly reduced CNV at the dose 6 mg/kg on the first day before and followed by 3 mg/kg on the third day after laser injury. The CNV volumes were analyzed with isolectin GS‐IB4 staining on choroidal/RPE flat mounts on the seventh day after laser injury. Injection of L‐ABH did not produce negative effects on retinal function and visual behavior. To dissect the mechanism in vitro, pretreatment with L‐ABH in primary RPE cultures significantly reduced production of vascular endothelial growth factor (VEGF) and macrophage chemotactic protein 1 (MCP‐1) by TNF&agr;‐primed RPEs. Consistent with these observations, L‐ABH pretreatment significantly attenuated macrophage migration mediated by TNF&agr;‐primed RPE. Collectively, intravenous injection of L‐ABH significantly reduced CNV volumes via reducing production of VEGF and MCP‐1 by inflammation‐primed RPEs. Graphical abstract We identify that intravenous injection of L‐ABH significantly attenuates CNV by laser injury without negative effect on retinal function and visual behavior. The reducing effect on CNV is mediated via antagonizing VEGF and MCP‐1 production by inflammation‐primed RPEs. Figure. No Caption available. HighlightsIntravenous injection of l‐Aspartic acid &bgr;‐hydroxamate (L‐ABH) reduced choroidal neovascularization induced by laser injury.Intravenous injection of L‐ABH did not pose negative effect on retinal function and visual behavior.Injection of L‐ABH increased L‐serine content and L/D‐serine ratios in aqueous humor.L‐ABH inhibited production of MCP‐1, VEGF by inflammation‐primed RPEs.

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