Anti-Inflammatory Potency of Oral Disulfiram Compared with Dexamethasone on Endotoxin-Induced Uveitis in Rats

Abstract

ABSTRACT. To investigate potency of oral disulfiram (DSF) compared with that of dexamethasone (Dexa), on endotoxin-induced uveitis (EIU) in rats. The oral administration with 750 mg/kg DSF suppressed the number of inflammatory cells, protein concentration, and levels of tumor necrosis factor (TNF)-, Nitric oxide (NO) and prostaglandin (PG) E2 in the aqueous humor and improved the histiologic status of the ocular tissue at 24 hr after lipopolysaccharide (LPS) injection. The anti-inflammatory potency of DSF oral administration was as strong as that observed with 0.5 mg/kg Dexa in the present study. The results suggest that DSF might pave the way for a novel therapeutic agent for the management of uveitis.KEY WORDS: anti-inflammatory potency, dexamethasone, diethyldithiocarbamate, disulfiram, endotoxin-induced uveitis.J. Vet. Med. Sci. 73(4): 517-520, 2011 Endotoxin-induced uveitis (EIU) is an animal model for acute ocular inflammation [17]. In general, cellular inflammation in EIU starts 4 hr after injection of LPS, with maximum infiltration after 18-24 hr [24]. The Although the contributions of tumor necrosis factor (TNF)-α are pleiotropic [10,16,18], the TNF-α, Interleukin (IL)-1β and IL-6 are considered to be particularly essential in the pathogenesis of EIU [3,4,25]. Nitric oxide (NO) [8] and prostaglandin (PG) E2 [1] are also involved in the pathogenesis of EIU. Disulfirum (DSF), as a prodrug of diethyldithiocarbamate (DDC), has long been used for the treatment of alcoholic syndrome without severe side effects [14]. DSF is cleaved into DDC within the gastrointestinal tract by oral administration. DSF has been reported to have multiple biological properties, including anti-inflammatory [23], anti-cataract [7], and anti-tumor properties [2]. We previously reported that oral DSF administration significantly reduced the development of EIU in a dose-dependent manner and 750 mg/kg DSF was most effective in inhibiting LPS-induced elevation of number of infiltrating cells, protein concentration and inflammatory mediators in aqueous humor [9], but did not compare DSF with corticosteroids which was the primary treatments available for uveitis. In our present study, therefore, we focused our attention on the antiinflammatory potency of 750 mg/kg DSF compared with that of 0.5 mg/kg dexamethasone (Dexa).Seven-week-old male Lewis rats were used. The rats weighed 180-220 g. After appropriately anesthetized with isoflurane, EIU was induced by injection into one footpad of 200 μg of LPS from Salmonella typhimurium (Sigma-Aldrich, St. Louis, MO, U.S.A.) that had been diluted in 0.1 ml of phosphate buffered saline (pH 7.4 PBS). Rats were orally administered 750 mg/kg of DSF (Sigma-Aldrich) diluted in 0.4 ml of 0.5% w/v dimethyl sulfoxide (DMSO; Sigma-Aldrich). DSF was orally administered 1 hr prior to LPS injection via gastic gavage. For the LPS and control group, 0.4 ml of 0.5% w/v DMSO was given orally on the same schedule as the DSF group. Dexa was administered in rats as described previously [15]. Briefly, animals were ...

DETC-based bacterial cellulose bio-curatives for topical treatment of cutaneous leishmaniasis

“…Although IFN-γ and TNF are key molecules for macrophage activation and leishmania killing, excessive inflammation is related to tissue damage and the development of more severe clinical manifestations of CL204647. In accordance, Dissulfiram suppressed TNF, NO and PGE 2 release after LPS injection48 and it also significantly inhibited the release of LPS-induced metalloproteinases and TNF via an increase in superoxide release49.…”

Tyrosol ameliorates lipopolysaccharide-induced ocular inflammation in rats via inhibition of nuclear factor (NF)-κB activation

“…Sagittal sections (3 µ m) were cut near the optic nerve head and stained with hematoxylin and eosin (H&E). The histopathologic evaluation of the anterior chamber, ICB, vitreous and retina in the EIU rats was scored (Grade, 0 to 3) using a light microscope [ 21 ]. Grade 0 represents no infiltrating cells; grade 1 represents mild cell infiltration; grade 2 represents moderate cell infiltration; and grade 3 represents severe cell infiltration in the ocular tissues.…”

Application of Disulfiram and its Metabolites in Treatment of Inflammatory Disorders

“…The main pathophysiological characteristics are infiltration of inflammatory cells and accumulation of inflammatory factors in aqueous humor (Mo et al, 1999). DSF can dosedependently reduce inflammatory cells infiltration and protein concentration in aqueous humor of LPS-induced rat model of uveitis, and decrease the levels of inflammatory factors such as NO, TNF-α and PGE2 in aqueous humor (Kanai et al, 2010;Kanai et al, 2011). However, its mechanism needs to be further elucidated.…”