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NSAIDs inhibit neovascularization of choroid through HO-1-dependent pathway

Narimasa Yoshinaga1, Noboru Arimura, Hiroki Otsuka

  • 1Department of Ophthalmology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Laboratory Investigation; a Journal of Technical Methods and Pathology
|June 29, 2011
PubMed

Insights

Topical non-steroidal anti-inflammatory drugs (NSAIDs) show promise for treating choroidal neovascularization (CNV). These drugs activate anti-stress protein heme oxygenase-1 (HO-1), reducing CNV lesion size and inflammation.

Area of Science:

  • Ophthalmology
  • Molecular Biology
  • Pharmacology

Background:

  • Intraocular neovascularization, particularly choroidal neovascularization (CNV), is a major cause of vision loss.
  • Current anti-vascular endothelial growth factor (VEGF) therapies for CNV have safety concerns.
  • Non-steroidal anti-inflammatory drugs (NSAIDs) possess anti-stress properties with potential therapeutic applications.

Purpose of the Study:

  • To investigate the effects of topical NSAIDs on CNV.
  • To explore the role of anti-stress proteins, specifically NF-E2-related factor 2 (Nrf2) and heme oxygenase (HO)-1, in NSAID-mediated CNV inhibition.
  • To evaluate the therapeutic potential of topical bromfenac in a rat model of laser-induced CNV.

Main Methods:

  • Cultured retinal pigment epithelium (RPE) cells were treated with bromfenac or indomethacin.
  • Western blot and immunohistochemistry were used to assess Nrf2 and HO-1 expression.
  • Laser-induced CNV model in rats was used to evaluate the effects of topical bromfenac, including lesion size, macrophage infiltration, and VEGF levels.
  • The role of HO-1 was assessed using an inhibitor (stannic mesoporphyrin, SnMP).

Main Results:

  • NSAIDs induced Nrf2 nuclear translocation and HO-1 expression in RPE cells in a dose- and time-dependent manner.
  • Bromfenac inhibited H(2)O(2)-induced apoptosis in RPE cells.
  • Topical bromfenac in rats led to Nrf2 translocation and HO-1 induction in CNV lesions, decreasing macrophage infiltration and CNV lesion size.
  • The anti-CNV effects of bromfenac were diminished by SnMP, and both bromfenac and SnMP inhibited VEGF.

Conclusions:

  • Topical NSAIDs, particularly bromfenac, inhibit CNV through a novel heme oxygenase-1 (HO-1)-dependent pathway.
  • This pathway involves the activation of the anti-stress protein Nrf2.
  • NSAIDs demonstrate potential therapeutic value for intraocular angiogenic diseases like CNV.

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