title: Inhibitory effects of oral disulfiram on endotoxin-induced uveitis in rats.
abstract: OBJECTIVE
  Disulfiram (DSF) exhibits a wide variety of biological activities, including an anti-inflammatory action, on which we focused our attention. The aim of the present study was to investigate the effect of oral DSF on endotoxin-induced uveitis (EIU) in rats.
  
  
  METHODS
  We investigated its effect upon cellular infiltration and protein leakage, as well as on the concentration of tumor necrosis factor-α (TNF-α), nitric oxide (NO), and prostaglandin E2 (PGE2) in the anterior chamber. Some eyes were enucleated for histologic examination and immunohistochemical analysis. EIU was induced in male Lewis rats by a footpad injection of lipopolysaccharide (LPS). One hour before the LPS injection, either 250, 500, or 750 mg/kg DSF was administered orally. Twenty-four hours later, the aqueous humor was collected from both eyes, and the number of infiltrating cells and protein concentration in the aqueous humor were determined. Levels of TNF-α, NO, and PGE2 were determined by enzyme-linked immunosorbent assay. Immunohistochemical analysis in the iris ciliary body (ICB) cells was performed to determine the expression of activated nuclear factor kappa B (NF-κB), inducible-nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2).
  
  
  RESULTS
  The oral administration with DSF suppressed, in a dose-dependent manner, the number of inflammatory cells, the protein concentration, and the levels of TNF-α, NO, and PGE2 in the aqueous humor and improved the histiologic status of the ocular tissue. The expression of activated NF-κB-positive cells in the ICB was significantly inhibited by oral administrated with DSF 3 hr after the LPS injection. The LPS-induced increased expressions of iNOS and COX-2 proteins in the ICB were also inhibited by oral DSF 24 hr after LPS injection.
  
  
  CONCLUSIONS
  The present results indicate that oral DSF suppresses the inflammation in EIU by inhibiting the NF-κB-dependent pathway and the subsequent production of pro-inflammatory mediators.
authors.affiliation: Department of Small Animal Internal Medicine, School of Veterinary Medicine, University of Kitasato, Towada, Aomori, Japan. kanai@vmas.kitasato-u.ac.jp
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Kanai
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Itoh
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Yonezawa
authors.forename: Hiromi
authors.initials: H
authors.lastname: Ikadai
authors.forename: Yasutomo
authors.initials: Y
authors.lastname: Hori
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Ito
authors.forename: Noriaki
authors.initials: N
authors.lastname: Nagai
authors.forename: Seishirou
authors.initials: S
authors.lastname: Chikazawa
authors.forename: Fumio
authors.initials: F
authors.lastname: Hoshi
authors.forename: Seiichi
authors.initials: S
authors.lastname: Higuchi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D001082:Aqueous Humor / Q000187:drug effects / Q000378:metabolism*; D002924:Ciliary Body / Q000187:drug effects / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D015232:Dinoprostone / Q000037:antagonists & inhibitors; D004221:Disulfiram / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004334:Drug Administration Schedule; D004731:Endotoxins; D005136:Eye Proteins / Q000037:antagonists & inhibitors; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009994:Osmolar Concentration; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014605:Uveitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*
chemical_list: D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D004731:Endotoxins; D005136:Eye Proteins; D018836:Inflammation Mediators; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D015232:Dinoprostone; D004221:Disulfiram