title: The HIF-1 antagonist acriflavine: visualization in retina and suppression of ocular neovascularization.
abstract: Acriflavine, a fluorescent drug previously used for bacterial and trypanosomal infections, reduces hypoxia-inducible factor-1 (HIF-1) and HIF-2 transcriptional activity. In mice with oxygen-induced ischemic retinopathy, intraocular or intraperitoneal injections of acriflavine caused dose-dependent suppression of retinal neovascularization (NV) and significantly reduced expression of HIF-1-responsive genes. Intraocular injection of 100 ng caused inner retina fluorescence within 1 h that was seen throughout the entire retina between 1 and 5 days, and at 7 days after injection, strongly suppressed choroidal NV at Bruch's membrane rupture sites. After suprachoroidal injection of 300 ng in rats, there was retinal fluorescence in the quadrant of the injection at 1 h that spread throughout the entire retina and choroid by 1 day, was detectable for 5 days, and dramatically reduced choroidal NV 14 days after rupture of Bruch's membrane. After topical administration of acriflavine in mice, fluorescence was seen in the retina and retinal pigmented epithelium within 5 min and was detectable for 6-12 h. Administration of 0.5% drops to the cornea twice a day significantly reduced choroidal NV in mice. Electroretinographic b-wave amplitudes were normal 7 days after intravitreous injection of 100 ng of acriflavine in mice, showed mild threshold reductions at highest stimulus intensities after injection of 250 ng, and more extensive changes after injection of 500 ng. These data provide additional evidence for an important role for HIF-1 in retinal and choroidal NV and suggest that acriflavine can target HIF-1 through a variety of modes of administration and has good potential to provide a novel therapy for retinal and choroidal vascular diseases.
  
  
  
  Acriflavine, an inhibitor of HIF-1, suppresses retinal and choroidal neovascularization. HIF-1 plays a critical role in ocular neovascularization. Acriflavine's fluorescence provides a mean to track its entry and exit from the retina. Acriflavine has therapeutic potential for the treatment of ocular neovascularization.
authors.affiliation: Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Hainan Eye Hospital, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Mingbing
authors.initials: M
authors.lastname: Zeng
authors.affiliation: Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Jikui
authors.initials: J
authors.lastname: Shen
authors.affiliation: Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Lucy Yang
authors.initials: LY
authors.lastname: Lu
authors.affiliation: Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Kun
authors.initials: K
authors.lastname: Ding
authors.affiliation: Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Seth D
authors.initials: SD
authors.lastname: Fortmann
authors.affiliation: Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Mahmood
authors.initials: M
authors.lastname: Khan
authors.affiliation: Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Jiangxia
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Sean F
authors.initials: SF
authors.lastname: Hackett
authors.affiliation: Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.|Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.affiliation: Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. pcampo@jhmi.edu.|Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. pcampo@jhmi.edu.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
mesh_terms: D000167:Acriflavine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000473:pathology; D016903:Drug Monitoring; D005456:Fluorescent Dyes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors*; D056965:Injections, Intraocular; D008297:Male; D008810:Mice, Inbred C57BL; D061848:Optical Imaging; D051381:Rats; D012160:Retina / Q000187:drug effects* / Q000473:pathology; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000473:pathology
chemical_list: D005456:Fluorescent Dyes; D051793:Hypoxia-Inducible Factor 1; D000167:Acriflavine
keywords: Age-related macular degeneration; Diabetic retinopathy; Ischemia; Suprachoroidal injection; Vascular endothelial growth factor