Histamime Receptor H4 as a New Therapeutic Target for Age-related Macular Degeneration

Histamine receptor H4 (HRH4) is one of four known histamine receptors, among which H1 receptor is primarily involved in typeI allergic reactions and H2 receptor is generally recognized for its role in gastric acid secretion. Compared with H1 and H2, HRH4 has unique characteristics; it is expressed in neurons and vascular endothelial cells, and is reported to be deeply involved in inflammation. Therefore, we investigated whether HRH4 is expressed in choroidal neovascularization(CNV), the main cause of age-related macular degeneration, and further examined whether HRH4-targeted treatment is effective in suppressing CNV. It was determined that HRH4 was expressed in human and mouse CNV, but not in the normal state of mouse retina, retinal pigment epithelium, or choroid. Laser-induced CNV in Hrh4-deficient mice was significantly smaller compared with that in wild-type mice. Immunohistochemistry showed co-positivity of the macrophage marker F4/80 with HRH4-positive cells in laser-induced CNV. Intravitreal administration of an HRH4 antagonist reduced laser-induced CNV in wild-type mice. In addition, oral administration of an HRH4 antagonist also reduced laser-induced CNV. HRH4 antagonists had no effect on tube formation in human retinal vascular endothelial cells. We also examined retinal toxicity after HRH4 antagonist administration; no retinal degeneration was observed even when a large amount of HRH4 antagonist was injected into the mouse eyes, which was confirmed using fundus imaging, retinal histology, and electroretinography. In conclusion, HRH4 antagonist is believed to be a possible therapeutic agent that reduces CNV without causing retinal toxicity.