Suppression of laser-induced choroidal neovascularization by a CCR3 antagonist.

Abstract

PURPOSE:

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: Takeshi Mizutani, Masayuki Ashikari, Mayumi Tokoro, Miho Nozaki, Yuichiro Ogura
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 54 Issue 2 Pg. 1564-72 (Feb 28 2013) ISSN: 1552-5783 [Electronic] United States
• PMID: 23404125 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Ccl11 protein, mouse
• Ccr3 protein, mouse
• Chemokine CCL11
• Ki-67 Antigen
• N-(1-((6-fluoro-2-naphthyl)methyl)pyrrolidin-3-yl)-2-(1-((3-methyl-1-oxidopyridin-2-yl)carbonyl)piperidin-4-ylidene)acetamide
• Pyridinium Compounds
• RNA, Messenger
• Receptors, CCR3
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• rac1 GTP-Binding Protein

Topics

• Administration, Oral
• Amides (administration & dosage, pharmacology)
• Animals
• Blotting, Western
• Chemokine CCL11 (metabolism)
• Choroid (metabolism)
• Choroidal Neovascularization (etiology, genetics, metabolism, prevention & control)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Fluorescein Angiography
• Intravitreal Injections
• Ki-67 Antigen (metabolism)
• Laser Coagulation (adverse effects)
• Male
• Mice
• Mice, Inbred C57BL
• Microscopy, Confocal
• Pyridinium Compounds (administration & dosage, pharmacology)
• RNA, Messenger (metabolism)
• Real-Time Polymerase Chain Reaction
• Receptors, CCR3 (antagonists & inhibitors, metabolism)
• Retinal Pigment Epithelium (metabolism)
• Treatment Outcome
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• rac1 GTP-Binding Protein (metabolism)