title: Evaluation of treatment for dry eye with 2-hydroxyestradiol using a dry eye rat model.
abstract: OBJECTIVE
  2-hydroxy estradiol (2-OHE2) is a catechol derivative of 17β -Estradiol (E2) and it is synthesized from E2 catalyzed by cytochrome P4501A1. Previous studies reported that 2-OHE2 is a physiologic antioxidant in lipoproteins, liver microsomes, and the brain. Catechol derivatives show an anti-inflammatory effect through the inhibition of prostaglandin endoperoxide synthase (PGS) activity. Corneal erosion caused by dry eye is related to an increase in oxidative stress and inflammation in ocular surface cells. We investigated the therapeutic effects of 2-OHE2 on corneal damage caused by dry eye.
  
  
  METHODS
  Steroidal radical scavenging activity was confirmed through the electron spin resonance (ESR) method. PGS activity was measured using the COX Fluorescent Activity Assay Kit. To evaluate the effect of 2-OHE2 on the treatment for dry eye, 2-OHE2 was applied as an eye drop experiment using dry eye model rats.
  
  
  RESULTS
  2-OHE2 scavenged tyrosyl radical and possibly suppressed oxidative stress in corneal epithelial cells. In addition, 2-OHE2 inhibited PGS activity, and 2-OHE2 is probably a competitive inhibitor of PGS. Corneal PGS activity was upregulated in the dry eye group. Therefore, 2-OHE2 eye drops improved corneal erosion in dry eye model rats.
  
  
  CONCLUSIONS
  2-OHE2 is a candidate for the treatment of dry eye through the suppression of inflammation and oxidative stress in the cornea.
authors.affiliation: Shinanomachi Research Park 6N9, Center for Integrated Medical Research, Keio University, School of Medicine, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Higuchi
authors.affiliation: Shinanomachi Research Park 6N9, Center for Integrated Medical Research, Keio University, School of Medicine, Tokyo, Japan; Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Erina
authors.initials: E
authors.lastname: Oonishi
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kawakita
authors.affiliation: Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
mesh_terms: D000818:Animals; D002460:Cell Line; D003316:Corneal Diseases / Q000188:drug therapy* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015352:Dry Eye Syndromes / Q000188:drug therapy* / Q000378:metabolism; D004578:Electron Spin Resonance Spectroscopy; D019573:Epithelium, Corneal / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004958:Estradiol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009883:Ophthalmic Solutions; D018384:Oxidative Stress / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D016166:Free Radical Scavengers; D015850:Interleukin-6; D009883:Ophthalmic Solutions; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; C001390:2-hydroxyestradiol; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C489691:Ptgs2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat