Histamine H4 receptor as a new therapeutic target for choroidal neovascularization in age‐related macular degeneration. (August 2014)

• Record Type: Journal Article
• Authors: Kaneko, Hiroki; Ye, Fuxiang; Ijima, Ryo; Kachi, Shu; Kato, Seiichi; Nagaya, Masatoshi; Higuchi, Akiko; Terasaki, Hiroko
• Is Part Of: British journal of pharmacology. Volume 171:Number 15(2014:Aug.)
• Page Start: 3754
• Page End: 3763
• Publication Date: 2014-08
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.12737
• Languages: English
• ISSNs: 0007-1188

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bph12737-sec-0001" sec-type="section"> <title>Background and Purpose</title> <p>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 H<sub>4</sub> receptor expression on CNV in mice.</p> </sec> <sec id="bph12737-sec-0002" sec-type="section"> <title>Experimental Approach</title> <p>H<sub>4</sub> 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 <italic>H</italic><italic>rh4<sup>‐/‐</sup></italic> mice with laser CNV. The effects of JNJ7777120, an H<sub>4</sub> 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.</p> </sec> <sec id="bph12737-sec-0003" sec-type="section"> <title>Key Results</title> <p>Human H<sub>4</sub> receptors were only confirmed in CNV samples from AMD patients and not in the other subretinal tissues. Mouse H<sub>4</sub> 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 <italic>H</italic><italic>rh4<sup>‐/‐</sup></italic> 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.</p> </sec> <sec id="bph12737-sec-0004" sec-type="section"> <title>Conclusions and Implications</title> <p>H<sub>4</sub> receptors are expressed in macrophages that accumulate around CNVs. Suppressing H<sub>4</sub> receptor expression prevented the pathological vessel leakage without showing retinal toxicity, indicating that the H<sub>4</sub> receptor has potential as a novel therapeutic target in AMD.</p> </sec> </abstract>