PURPOSE: This study aimed to examine relationship of histamine receptor H4 (HRH4) and the pathogenesis of laser-induced choroidal neovascularization (laser-CNV) and to determine whether oral administration of HRH4 antagonists suppressed laser-CNV in mice. METHODS: Laser photocoagulation was performed in mice to induce the laser-CNV. Histamine was administered intravitreously, and CNV volume was measured. Laser photocoagulation and intravitreous injection of HRH4 antagonist JNJ7777120 were performed after intraperitoneal injection of clodronate liposome, which depletes circulating monocyte-derived macrophages; CNV volume was compared with that in mice injected with control (dimethyl sulfoxide [DMSO]/PBS). Three days after laser-CNV, the F4/80+CD11b+ macrophage population in retinal pigment epithelium (RPE)/choroid complex was quantified with flow cytometry in wild-type and Hrh4-/- mice. The long-acting HRH4 antagonist JNJ28307474 was then administrated periorally, and the laser-CNV volume was compared with controls. RESULTS: Intravitreous injection of histamine did not affect laser-CNV volume. The laser-CNV from the eye injected with JNJ7777120 was equivalent to that injected with the DMSO/PBS in mice that had intraperitoneally received clodronate liposome. Flow cytometry after laser-CNV induction revealed a smaller F4/80+CD11b+ macrophage population in the RPE/choroid complex of Hrh4-/- mice than in wild-type mice. Oral administration of JNJ28307474 significantly reduced laser-CNV volume in wild-type mice. CONCLUSIONS: Our results suggested that HRH4-positive macrophages played an important role in the pathogenesis of laser-CNV and that they require a different ligand from that of histamine. The oral administration of an HRH4 antagonist successfully reduced laser-CNV. TRANSLATIONAL RELEVANCE: Our results indicate that drugs targeting HRH4 are potentially a novel oral treatment for age-related macular degeneration.
PURPOSE: This study aimed to examine relationship of histamine receptor H4 (HRH4) and the pathogenesis of laser-induced choroidal neovascularization (laser-CNV) and to determine whether oral administration of HRH4 antagonists suppressed laser-CNV in mice. METHODS: Laser photocoagulation was performed in mice to induce the laser-CNV. Histamine was administered intravitreously, and CNV volume was measured. Laser photocoagulation and intravitreous injection of HRH4 antagonist JNJ7777120 were performed after intraperitoneal injection of clodronate liposome, which depletes circulating monocyte-derived macrophages; CNV volume was compared with that in mice injected with control (dimethyl sulfoxide [DMSO]/PBS). Three days after laser-CNV, the F4/80+CD11b+ macrophage population in retinal pigment epithelium (RPE)/choroid complex was quantified with flow cytometry in wild-type and Hrh4-/- mice. The long-acting HRH4 antagonist JNJ28307474 was then administrated periorally, and the laser-CNV volume was compared with controls. RESULTS: Intravitreous injection of histamine did not affect laser-CNV volume. The laser-CNV from the eye injected with JNJ7777120 was equivalent to that injected with the DMSO/PBS in mice that had intraperitoneally received clodronate liposome. Flow cytometry after laser-CNV induction revealed a smaller F4/80+CD11b+ macrophage population in the RPE/choroid complex of Hrh4-/- mice than in wild-type mice. Oral administration of JNJ28307474 significantly reduced laser-CNV volume in wild-type mice. CONCLUSIONS: Our results suggested that HRH4-positive macrophages played an important role in the pathogenesis of laser-CNV and that they require a different ligand from that of histamine. The oral administration of an HRH4 antagonist successfully reduced laser-CNV. TRANSLATIONAL RELEVANCE: Our results indicate that drugs targeting HRH4 are potentially a novel oral treatment for age-related macular degeneration.
Authors: M I Strakhova; C A Cuff; A M Manelli; T L Carr; D G Witte; J L Baranowski; T A Vortherms; T R Miller; L Rundell; M J McPherson; R M Adair; A A Brito; B M Bettencourt; B B Yao; J M Wetter; K C Marsh; H Liu; M D Cowart; J D Brioni; T A Esbenshade Journal: Br J Pharmacol Date: 2009-05 Impact factor: 8.739