insight into the possible protective effect of pyrrolidine dithiocarbamate against lipopolysaccharide- induced oxidative stress and acute hepatic injury in rats

Lipopolysaccharide [LPS] is a major cell wall molecule of Gram-negative bacteria known to stimulate the synthesis and secretion of several toxic metabolites, such as reactive oxygen species. In this study, the effect of pyrrolidine dithiocarbamate [PDTC], an antioxidant with nuclear factor- kappa B inhibitor activity, was evaluated in LPS-induced oxidative stress and acute hepatic injury in rats. Animals were pre-treated for 3 consecutive days with PDTC[200 mg/kg/day, i.p.] or saline and animals were then challenged with LPS[6 mg/kg, i.p.] or saline. Six hours after LPS injection, animals were decapitated and blood and liver samples were collected to assess the chosen biochemical parameters. Saline-pretreated animals challenged with LPS revealed extensive liver damage, as evidenced by increase in serum levels of alanine aminotransferase [ALT], aspirate aminotransferase [AST] and gamma glutamyl transferase [gamma -GT]. Also, LPS treatment resulted in significant increases in serum lactate dehydrogenase [LDH], tumor necrosis factor-alpha [TNF- alpha] and nitrite levels. Furthermore, LPS challenge caused oxidative stress as indicated by an increase in hepatic lipid peroxidation measured as thiobarbituric acid reactive substances [TBARS] and a decrease in hepatic reduced glutathione concentration [GSH] as well as decreased activities of superoxide dismutase [SOD] and [GSH] as well as decreased activities of superoxide dismutase [SOD] and catalase in hepatic tissues. The administration of PDTC prior to LPS challenge resulted in improved liver functions as evidenced by the decline in serum AST, ALT, gamma-GT levels and reduction in serum LDH, TNF- alpha and nitrite levels. Moreover, PDTC reduced the chosen lipid peroxidation marker, TBARS and increased GSH concentration, and SOD and catalase activities in hepatic tissues. These results indicate that PDTC may be a useful pharmacological agent in alleviating LPS-induced oxidative stress and acute hepatic injury

Cysteinyl leukotriene receptor blocker, zafirlukast attenuates lipopolysaccharide -induced oxidative injury and multiple organ dysfunction in rats

Lipopolysaccharide [LPS] is a key mediator of multiple organ injury observed in septic shock. Leukotrienes have been shown to be involved in many inflammatory conditions. However, their role in septic shock has not been fully investigated. The major focus of the present study is to determine the effect of cysteinyl leukotriene blocker, zafirlukast on LPS-induced multiple organ dysfunction in experimental rats. Induction of endotoxemia for 6 h with a single intraperitoneal injection of LPS [6 mg/kg] resulted in 30% mortality rate. Animals challenged with LPS also revealed increases in serum levels of lactate dehydrogenase [LDH], a marker of systemic tissue injury, bilirubin, and serum aminotransferases, alanine aminotransferase [ALT] and aspartate aminotransferase [AST] as measures of hepatic damage, blood urea nitrogen and serum creatinine levels [renal dysfunction indicators], creatine kinase-MB activity [heart injury indicator] and amylase [pancreatic injury measure]. Furthermore, LPS administration produced significant increases in serum levels of tumor necrosis factor-alpha [TNF- alpha], interleukin- 1 p [IL-lp], nitric oxide [NO] and intercellular adhesion molecules- 1 [ICAM-1] suggesting activation of the proinflammatory response. Oxidative stress was evident by significant increments in lipid peroxides concentrations measured as thiobarbituric acid reactive substances [TBARS] and decrements in reduced glutathione [GSH] concentrations in liver, kidney, pancreas and heart of LPS-treated animals. Myeloperoxidase [MPO] activity, a neutrophil infiltration marker, was also elevated in the same tissues. Administration of zafirlukast in two different doses [40 and 80 mg/kg/day, orally via gavage] for three consecutive days prior to LPS injection decreased LPS-induced lethality, attenuated multiple organ injury and dysfunction and reduced the increases in serum levels of TNF-alpha, IL-1beta, total nitrite/nitrate and ICAM-1. Also, MPO activities and TBARS concentrations were suppressed while GSH contents were increased in tissues. These results indicate that zafirlukast protects against LPS-induced multiple organ damage by inhibiting neutrophil infiltration, counteracting oxidative stress and suppression of inflammatory mediators. Zafirlukast may serve as a potentially effective prophylactic pharmacological agent in alleviating LPS-induced multiple organ dysfunction

Renal ischemia -reperfusion injury: contribution of nitric oxide and reactive oxygen species

The present study was undertaken to examine the effect of ischemia/reperfusion injury to the kidney on basal NO production and to define whether the antioxidants or NO precursor can modulate NO production in this model or not. Induction of renal ischemia for 60 minutes followed by 15 minutes reperfusion in adult male Wistar rats resulted into impairment of NO production as indicated by reduced serum nitrite/nitrate levels, increase in lipid peroxidation measured as malondialdehyde [MDA] and depletion of reduced glutathione [GSH] and catalase contents in rat kidney. NO precursor, L-arginine [L-ARG] as well as hydroxyl radical scavengers, dimethylthiourea [DMTU] and an iron chelator, deferoxamine [DFO] increased serum NO level and renal GSH and catalase levels and reduced renal MDA. Conversely, infusion of iron complex EDTA-FeCl3 10 minutes before ischemia exacerbated the changes in the parameters studied was induced by ischemia/reperfusion