Abstract
PurposeTo investigate the effects of curcumin on the development of experimental choroidal neovascularization (CNV) with underlying cellular and molecular mechanisms.MethodsC57BL/6N mice were pretreated with intraperitoneal injections of curcumin daily for 3 days prior to laser-induced CNV, and the drug treatments were continued until the end of the study. The CNV area was analyzed by fluorescein-labeled dextran angiography of retinal pigment epithelium (RPE)-choroid flat mounts on day 7 and 14, and CNV leakage was evaluated by fluorescein angiography (FA) on day 14 after laser photocoagulation. The infiltration of F4/80 positive macrophages and GR-1 positive granulocytes were evaluated by immunohistochemistry on RPE-choroid flat mounts on day 3. Their expression in RPE-choroid complex was quantified by real-time PCR (F4/80) and Western blotting (GR-1) on day 3. RPE-choroid levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1, and intercellular adhesion molecule (ICAM)-1 were examined by ELISA on day 3. Double immunostaining of F4/80 and VEGF was performed on cryo-sections of CNV lesions on day 3. The expression of nuclear factor (NF)-κB and hypoxia-inducible factor (HIF)−1α in the RPE-choroid was determined by Western blotting.ResultsCurcumin-treated mice had significantly less CNV area (P<0.05) and CNV leakage (P<0.001) than vehicle-treated mice. Curcumin treatment led to significant inhibition of F4/80 positive macrophages (P<0.05) and GR-1 positive granulocytes infiltration (P<0.05). VEGF mainly expressed in F4/80 positive macrophages in laser injury sites, which was suppressed by curcumin treatment (P<0.01). Curcumin inhibited the RPE-choroid levels of TNF-α (P<0.05), MCP-1 (P<0.05) and ICAM-1 (P<0.05), and suppressed the activation of NF-κB in nuclear extracts (P<0.05) and the activation of HIF−1α (P<0.05).ConclusionCurcumin treatment led to the suppression of CNV development together with inflammatory and angiogenic processes including NF-κB and HIF−1α activation, the up-regulation of inflammatory and angiogenic cytokines, and infiltrating macrophages and granulocytes. This provides molecular and cellular evidence of the validity of curcumin supplementation as a therapeutic strategy for the suppression of age-related macular degeneration (AMD)-associated CNV.
Highlights
Age-related macular degeneration (AMD) is the leading cause of blindness among elderly people in developed countries [1]
Experimental and clinical studies have revealed that macrophages accumulate in choroidal neovascularization (CNV) area and express a variety of cytokines, including vascular endothelial growth factor (VEGF), which is recognized as a key signal in promoting angiogenesis and critical for CNV formation [6,7,8]
An analysis of retinal pigment epithelium (RPE)-choroid flatmounts showed the distinct reduction in CNV area after curcumin treatment (Fig. 1A)
Summary
Age-related macular degeneration (AMD) is the leading cause of blindness among elderly people in developed countries [1]. The pathogenic mechanisms underlying CNV are complex and still largely unknown, increasing amounts of evidence indicate that inflammatory and angiogenic events, including inflammatory cells infiltration and cytokine networks, play crucial roles in the development of CNV [3,4,5]. Experimental and clinical studies have revealed that macrophages accumulate in CNV area and express a variety of cytokines, including vascular endothelial growth factor (VEGF), which is recognized as a key signal in promoting angiogenesis and critical for CNV formation [6,7,8]. In mice that show pharmacologic depletion of macrophages, CNV is reduced when VEGF is reduced [3,4,5,6,7,8,9]. Granulocytes have been found to influx into laser induced CNV lesions and its depletion correlated with reduced CNV responses and decreased
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