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Journal of Molecular Medicine

, Volume 95, Issue 4, pp 417–429 | Cite as

The HIF-1 antagonist acriflavine: visualization in retina and suppression of ocular neovascularization

  • Mingbing Zeng
  • Jikui Shen
  • Yuanyuan Liu
  • Lucy Yang Lu
  • Kun Ding
  • Seth D. Fortmann
  • Mahmood Khan
  • Jiangxia Wang
  • Sean F. Hackett
  • Gregg L. Semenza
  • Peter A. Campochiaro
Original Article

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.

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.

Keywords

Age-related macular degeneration Diabetic retinopathy Ischemia Suprachoroidal injection Vascular endothelial growth factor 

Notes

Acknowledgements

This study is supported by EY012609 from the National Eye Institute.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Mingbing Zeng
    • 1
    • 2
    • 3
  • Jikui Shen
    • 1
    • 2
  • Yuanyuan Liu
    • 1
    • 2
  • Lucy Yang Lu
    • 1
    • 2
  • Kun Ding
    • 1
    • 2
  • Seth D. Fortmann
    • 1
    • 2
  • Mahmood Khan
    • 1
    • 2
  • Jiangxia Wang
    • 1
  • Sean F. Hackett
    • 1
    • 2
  • Gregg L. Semenza
    • 1
    • 2
  • Peter A. Campochiaro
    • 1
    • 2
  1. 1.Institute for Cell Engineering, McKusick-Nathans Institute of Genetic MedicineJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological ChemistryJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Hainan Eye Hospital, Zhongshan Ophthalmic CenterSun Yat-Sen UniversityGuangzhouChina

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