title: Suppression of laser-induced choroidal neovascularization by a CCR3 antagonist.
abstract: OBJECTIVE
  To evaluate the efficacy of a novel CCR3 antagonist for laser injury-induced choroidal neovascularization (CNV) in mice.
  
  
  METHODS
  We evaluated YM-344031, a novel and selective small-molecule CCR3 antagonist. CNV was induced by laser injury in C57BL/6J mice, and its volume was measured after 7 days by confocal microscopy. Leakage from the CNV was also measured after 7 days by fluorescein angiography. The CCR3 antagonist was administered by gavage at 1 hour before and 1 day after the laser injury, or intravitreous injection immediately after the laser injury. After the laser injury, ELISA, Western blot analysis, and real-time RT-PCR for VEGF-A expression in the RPE/choroid, and immunohistochemistry for CCR3, CCL11, Ki67, and Rac1 was performed.
  
  
  RESULTS
  Both oral administration and intravitreous injection of YM-344031 significantly suppressed the CNV volume (P < 0.0001 and P < 0.01, respectively). Pathologically significant leakage was significantly less common in YM-344031-injected mice (P < 0.0001). The mean VEGF protein level was significantly increased in vehicle-injected eyes after the laser injury (P < 0.05). Although the YM-344031-injected eyes did not show VEGF-A suppression after the laser injury, VEGF164 mRNA upregulation was significantly suppressed in YM-344031-injected mice (P < 0.05), and intravitreous injection of YM-344031 appeared to suppress CCR3, CCL11 (eotaxin), Ki67, and Rac1 expression after the laser injury.
  
  
  CONCLUSIONS
  The present data suggest that the CCR3 antagonist YM-344031 can suppress CNV, via suppression of the upregulation of VEGF164 mRNA in VEGF isoform after the laser injury. Although our findings may warrant further investigation, YM-344031 may have potential as a new therapy for age-related macular degeneration.
authors: Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors: Takeshi
authors: T
authors: Mizutani
authors: Masayuki
authors: M
authors: Ashikari
authors: Mayumi
authors: M
authors: Tokoro
authors: Miho
authors: M
authors: Nozaki
authors: Yuichiro
authors: Y
authors: Ogura
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D054413:Chemokine CCL11 / Q000378:metabolism; D002829:Choroid / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005451:Fluorescein Angiography; D058449:Intravitreal Injections; D019394:Ki-67 Antigen / Q000378:metabolism; D017075:Laser Coagulation / Q000009:adverse effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D011726:Pyridinium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D054397:Receptors, CCR3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000378:metabolism; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000577:Amides; C515457:Ccl11 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D019394:Ki-67 Antigen; C508080:N-(1-((6-fluoro-2-naphthyl)methyl)pyrrolidin-3-yl)-2-(1-((3-methyl-1-oxidopyridin-2-yl)carbonyl)piperidin-4-ylidene)acetamide; D011726:Pyridinium Compounds; D012333:RNA, Messenger; D054397:Receptors, CCR3; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D020830:rac1 GTP-Binding Protein