title: The effects of 2% rebamipide ophthalmic solution on the tear functions and ocular surface of the superoxide dismutase-1 (sod1) knockout mice.
abstract: OBJECTIVE
  To investigate the efficacy of 2% rebamipide ophthalmic solution on the tear functions and ocular surface status of the superoxide dismutase-1(Sod1(-/-)) mice.
  
  
  METHODS
  Two percent Rebamipide ophthalmic solution was applied to 40-week-old male Sod1(-/-) and wild-type (WT) mice four times a day for 2 weeks. We examined the cytokine concentrations in the tear fluid (by CytoBead assay), tear film break-up time, amount of tear production, and expressions of mucins 1, 4, and 5AC, by RT-PCR. We also performed vital staining of the ocular surface, PAS staining for muc5AC, and immunohistochemical stainings for 4-hydroxy-2-nonenal (4-HNE), 8-hydroxy-2'-deoxyguanosine (8-OHdG), in the conjunctiva to compare the results before and after rebamipide instillations.
  
  
  RESULTS
  The tear functions and ocular surface epithelial damage scores were significantly worse in the Sod1(-/-) than in the WT mice. Application of 2% rebamipide for 2 weeks significantly improved the tear film break-up time, the amount of tear production, and the corneal epithelial damage scores, which also significantly increased the conjunctival goblet cell density and muc5 mRNA expression, in the Sod1(-/-) mice. The mean IL-6, IL-17, TNF-α, and IFN-γ levels in the tear fluid were reduced significantly along with a significant decrease in the density of cells positive for 4-HNE and 8-OHdG in the conjunctiva.
  
  
  CONCLUSIONS
  Two percent Rebamipide ophthalmic solution significantly improved the tear stability and corneal epithelial damage, and enhanced the expression of muc5 mRNA on the ocular surface. We also observed anti-inflammatory effects in the tear film together with antioxidative effects in the conjunctiva, suggesting the efficacy of rebamipide in age-related dry eye disease attributable to SOD1 knockout.
authors.affiliation: Department of Ophthalmology, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ohguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kojima
authors.forename: Osama M
authors.initials: OM
authors.lastname: Ibrahim
authors.forename: Taeko
authors.initials: T
authors.lastname: Nagata
authors.forename: Takahiko
authors.initials: T
authors.lastname: Shimizu
authors.forename: Takuji
authors.initials: T
authors.lastname: Shirasawa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kawakita
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Satake
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tsubota
authors.forename: Jun
authors.initials: J
authors.lastname: Shimazaki
authors.forename: Susumu
authors.initials: S
authors.lastname: Ishida
mesh_terms: D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000818:Animals; D003228:Conjunctiva / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015352:Dry Eye Syndromes / Q000188:drug therapy* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009883:Ophthalmic Solutions; D015363:Quinolones / Q000008:administration & dosage*; D013482:Superoxide Dismutase / Q000172:deficiency; D000072105:Superoxide Dismutase-1; D013666:Tears / Q000187:drug effects / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D009883:Ophthalmic Solutions; D015363:Quinolones; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C052785:rebamipide; D000409:Alanine
keywords: dry eyes; inflammation; secretagogue