British Journal of Pharmacology 2014-08-01

Histamine H4 receptor as a new therapeutic target for choroidal neovascularization in age-related macular degeneration.

Hiroki Kaneko, Fuxiang Ye, Ryo Ijima, Shu Kachi, Seiichi Kato, Masatoshi Nagaya, Akiko Higuchi, Hiroko Terasaki

Index: Br. J. Pharmacol. 171(15) , 3754-63, (2014)

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Abstract

The present treatment for choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD) is not sufficient. Hence, we examined the therapeutic efficacy of reducing histamine H4 receptor expression on CNV in mice.H4 receptor expression was examined in CNVs from patients with AMD. In mice, laser photocoagulation was performed in the retina to induce experimental CNV (laser CNV). Protein and mRNA expression levels were determined and CNV volume measured in wild-type and Hrh4(-/-) mice with laser CNV. The effects of JNJ7777120, an H4 receptor antagonist, administered intravitreously, on CNV volume and pathological vessel leakage were determined in mice with laser CNV and controls. Fundus imaging, retinal histology and electroretinography were performed on eyes injected with JNJ7777120 to evaluate retinal toxicity.Human H4 receptors were only confirmed in CNV samples from AMD patients and not in the other subretinal tissues. Mouse H4 receptors were expressed in retinal pigment epithelium only after inducing laser CNV in wild-type mice, and were co-localized with the macrophage marker F4/80. Laser CNV volume was reduced in Hrh4(-/-) mice compared with that in wild-type mice, and JNJ7777120 suppressed laser-induced CNV volume and pathological CNV leakage in wild-type mice. Also eyes injected with JNJ7777120 did not show retinal degeneration.H4 receptors are expressed in macrophages that accumulate around CNVs. Suppressing H4 receptor expression prevented the pathological vessel leakage without showing retinal toxicity, indicating that the H4 receptor has potential as a novel therapeutic target in AMD.© 2014 The British Pharmacological Society.