Effects of Instillation of Eyedrops Containing Disulfiram and Hydroxypropyl-β-Cyclodextrin Inclusion Complex on Endotoxin-Induced Uveitis in Rats

Objective: To investigate the anti-inflammatory effects of the instillation of disulfirum (DSF) eyedrops that enhance solubility using 2-hydroxypropyl-beta-cyclodextrin (HP beta CD) and hydroxypropylmethylcellulose (HPMC) on endotoxin-induced uveitis (EIU) in rats and mechanisms related to ocular inflammation. Methods: EIU was induced in male Lewis rats by subcutaneous injection of 200 mu g lipopolysaccharide (LPS). DSF (0.125%, 0.25% and 0.5%) or commercially available 0.05% dexamethasone (Dexa) was topically applied to both eyes of rats 1 hour before, immediately after, and 1 and 2 hours after injection of LPS. The aqueous humor (AqH) was collected 24 hours after LPS injection, and the number of infiltrating cells, protein concentration, and levels of tumor necrosis factor-alpha (TNF-alpha), nitric oxide (NO) and prostaglandin E2 (PGE2) were determined. Immunohistochemical analysis of the iris ciliary body (ICB) cells was performed to determine the expression of activated nuclear factor kappa B (NF-kappa B), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Results: The topical administration with DSF suppressed, in a dose-dependent manner, the number of inflammatory cells, the protein concentration, and the levels of NO, TNF-alpha and PGE2 in the AqH and improved the histologic status of the ocular tissue. The anti-inflammatory potency of 0.5% DSF treatment was as strong as that of 0.05% Dexa. Topical DSF treatment also suppressed the activated NF-kappa B 3 hours after LPS injection, and iNOS and COX-2 expression in the ICB 24 hours after LPS injection. Conclusions: The present results demonstrate that the topical instillation of DSF eyedrops suppresses the inflammation in EIU, suggesting a possible novel approach for the treatment of ocular inflammation.