title: A Novel Platelet-Activating Factor Receptor Antagonist Inhibits Choroidal Neovascularization and Subretinal Fibrosis.
abstract: Choroidal neovascularization (CNV) is a critical pathogenesis in age-related macular degeneration (AMD), the most common cause of blindness in developed countries. To date, the precise molecular and cellular mechanisms underlying CNV have not been elucidated. Platelet-activating factor (PAF) has been previously implicated in angiogenesis; however, the roles of PAF and its receptor (PAF-R) in CNV have not been addressed. The present study reveals several important findings concerning the relationship of the PAF-R signaling with CNV. PAF-R was detected in a mouse model of laser-induced CNV and was upregulated during CNV development. Experimental CNV was suppressed by administering WEB2086, a novel PAF-R antagonist. WEB2086-dependent suppression of CNV occurred via the inhibition of macrophage infiltration and the expression of proangiogenic (vascular endothelial growth factor) and proinflammatory molecules (monocyte chemotactic protein-1 and IL-6) in the retinal pigment epithelium-choroid complex. Additionally, WEB2086-induced PAF-R blockage suppresses experimentally induced subretinal fibrosis, which resembles the fibrotic subretinal scarring observed in neovascular AMD. As optimal treatment modalities for neovascular AMD would target the multiple mechanisms of AMD-associated vision loss, including neovascularization, inflammation and fibrosis, our results suggest PAF-R as an attractive molecular target in the treatment of AMD.
authors.affiliation: Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan ; Department of Ophthalmology, the First Hospital of China Medical University, Shenyang, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Atsunobu
authors.initials: A
authors.lastname: Takeda
authors.forename: Takeru
authors.initials: T
authors.lastname: Yoshimura
authors.forename: Yuji
authors.initials: Y
authors.lastname: Oshima
authors.forename: Koh-Hei
authors.initials: KH
authors.lastname: Sonoda
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Ishibashi
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology*; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006401:Hematologic Agents / Q000494:pharmacology*; D007834:Lasers; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012164:Retinal Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D001381:Azepines; D006401:Hematologic Agents; D010980:Platelet Membrane Glycoproteins; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086