PMID- 28004126 OWN - NLM STAT- MEDLINE DCOM- 20180213 LR - 20181113 IS - 1432-1440 (Electronic) IS - 0946-2716 (Print) IS - 0946-2716 (Linking) VI - 95 IP - 4 DP - 2017 Apr TI - The HIF-1 antagonist acriflavine: visualization in retina and suppression of ocular neovascularization. PG - 417-429 LID - 10.1007/s00109-016-1498-9 [doi] AB - 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. KEY MESSAGE: 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. FAU - Zeng, Mingbing AU - Zeng M AD - Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Hainan Eye Hospital, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, China. FAU - Shen, Jikui AU - Shen J AD - Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Liu, Yuanyuan AU - Liu Y AD - Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Lu, Lucy Yang AU - Lu LY AD - Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Ding, Kun AU - Ding K AD - Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Fortmann, Seth D AU - Fortmann SD AD - Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Khan, Mahmood AU - Khan M AD - Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Wang, Jiangxia AU - Wang J AD - Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Hackett, Sean F AU - Hackett SF AD - Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Semenza, Gregg L AU - Semenza GL AD - Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. AD - Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. FAU - Campochiaro, Peter A AU - Campochiaro PA AD - Institute for Cell Engineering, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. pcampo@jhmi.edu. AD - Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. pcampo@jhmi.edu. LA - eng GR - P30 EY001765/EY/NEI NIH HHS/United States GR - R01 EB016121/EB/NIBIB NIH HHS/United States GR - R01 EY012609/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20161221 PL - Germany TA - J Mol Med (Berl) JT - Journal of molecular medicine (Berlin, Germany) JID - 9504370 RN - 0 (Fluorescent Dyes) RN - 0 (Hypoxia-Inducible Factor 1) RN - 1T3A50395T (Acriflavine) SB - IM MH - Acriflavine/administration & dosage/pharmacokinetics/*therapeutic use MH - Animals MH - Choroidal Neovascularization/*drug therapy/pathology MH - Drug Monitoring MH - Fluorescent Dyes/administration & dosage/pharmacokinetics/*therapeutic use MH - Hypoxia-Inducible Factor 1/*antagonists & inhibitors MH - Injections, Intraocular MH - Male MH - Mice, Inbred C57BL MH - Optical Imaging MH - Rats MH - Retina/*drug effects/pathology MH - Retinal Neovascularization/*drug therapy/pathology PMC - PMC5357443 MID - NIHMS838302 OTO - NOTNLM OT - Age-related macular degeneration OT - Diabetic retinopathy OT - Ischemia OT - Suprachoroidal injection OT - Vascular endothelial growth factor COIS- Disclosure Statement: None of the authors have a conflict of interest EDAT- 2016/12/23 06:00 MHDA- 2018/02/14 06:00 PMCR- 2018/04/01 CRDT- 2016/12/23 06:00 PHST- 2016/07/11 00:00 [received] PHST- 2016/12/01 00:00 [accepted] PHST- 2016/11/14 00:00 [revised] PHST- 2016/12/23 06:00 [pubmed] PHST- 2018/02/14 06:00 [medline] PHST- 2016/12/23 06:00 [entrez] PHST- 2018/04/01 00:00 [pmc-release] AID - 10.1007/s00109-016-1498-9 [pii] AID - 10.1007/s00109-016-1498-9 [doi] PST - ppublish SO - J Mol Med (Berl). 2017 Apr;95(4):417-429. doi: 10.1007/s00109-016-1498-9. Epub 2016 Dec 21.