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Apoptosis

, Volume 22, Issue 11, pp 1441–1453 | Cite as

Protective effects of carbenoxolone, an 11β-HSD1 inhibitor, against chemical induced dry eye syndrome

  • Yoon-Ju Na
  • Kyoung-Jin Choi
  • Sung Bum Park
  • Hye-Rim Sung
  • Won Hoon Jung
  • Hee Youn Kim
  • Sang Dal Rhee
  • Ki Young Kim
Original Paper
  • 277 Downloads

Abstract

Dry eye syndrome (DES) is a disorder of the eye due to tear deficiency or excessive evaporation that causes damage to the eye and is associated with discomfort and dryness. 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) is an enzyme that converts inactive cortisone to active cortisol. Recently, 11β-HSD1 has been expressed in human and rodent eyes and has been recognized as a target of glaucoma. In this study, the therapeutic effects and underlying mechanisms of topical carbenoxolone, an 11β-HSD1 inhibitor, were investigated in benzalkonium chloride (BAC)-treated human conjunctival epithelial cells and a rat DES model. In the in vitro study, carbenoxolone dose-dependently inhibited cell death and 11β-HSD1 activity in BAC-treated human conjunctival epithelial cells. For the in vivo study, carbenoxolone or a solvent was administered to the BAC-induced DES model twice daily. BAC-treated rat eyes showed significant increases in ocular surface damage, a reduction of tears, decrease corneal thickness, corneal basement membrane destruction, apoptosis in the conjunctival epithelium, and expression of pro-inflammatory cytokines (TNF-α and IL-6) and 11β-HSD1. These effects of BAC were reversed by topical carbenoxolone treatment. These results demonstrate that carbenoxolone can prevent DES by inhibiting pro-inflammatory cytokine expression and cell death of the corneal and conjunctival epithelium via inhibition of both 11β-HSD1 activity and expression in the eyes of BAC-treated rats. It is suggested that topical 11β-HSD1 inhibitors may provide a new therapeutic window in the prevention and/or treatment of DES.

Graphical Abstract

Keywords

Dry eye syndrome 11β-Hydroxysteroid dehydrogenase type 1 Carbenoxolone Benzalkonium chloride Apoptosis Inflammation 

Abbreviations

DES

Dry eye syndrome

11β-HSD1

11β-Hydroxysteroid dehydrogenase 1

BAC

Bezalkonium chloride

IL-6

Interleukin-6

TNF-α

Tumor necrosis factor-α

HConEC

Human conjunctival epithelial cells

H&E

Hematoxylin & Eosin

PAS

Periodic Acid & Schiff’s

SD rat

Sprague–Dawley rat

TUNEL

Terminal deoxynucleotidyl transferase dUTP nick end labeling

Notes

Acknowledgements

We would like to acknowledge the financial support from the R&D Convergence Program (CCP-13-20-KRICT) and the DRC program (DRC-15-01-KRICT) of National Research Council of Science & Technology, and a project of the Korea Research Institute of Chemical Technology, the Ministry of Knowledge Economy, Republic of Korea.

Author Contributions

Participated in research design: Y-JN, K-JC, and KYK. Conducted experiments: Y-JN, K-JC, SBP, H-RS, WHJ, and HYK. Contributed new reagents or analytic tools: HYK, and SDR. Performed data analysis: Y-JN, SDR, and KYK. Wrote or contributed to the writing of the manuscript: Y-JN, and KYK.

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Yoon-Ju Na
    • 1
    • 2
  • Kyoung-Jin Choi
    • 1
  • Sung Bum Park
    • 1
  • Hye-Rim Sung
    • 1
  • Won Hoon Jung
    • 1
  • Hee Youn Kim
    • 1
  • Sang Dal Rhee
    • 1
  • Ki Young Kim
    • 1
    • 2
  1. 1.Bio & Drug Discovery DivisionKorea Research Institute of Chemical TechnologyDaejeonRepublic of Korea
  2. 2.Department of New Drug Discovery and DevelopmentChungnam National UniversityDaejeonRepublic of Korea

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