Antioxidant-statin combination for the management of intraperitoneal sepsis in rats

There is a good evidence that endotoxemia, sepsis, and septic shock are associated with the generation and release of reactive oxygen species [ROS], indicating that oxygen-derived free radicals play an important role in the pathogenesis of septic shock. Inhibitors of HMG-CoA reductase in addition to lowering serum cholesterol levels, exert many pleiotropic effects as antioxidant and anti-inflammatory action. The present study was designed to investigate the possible modulatory effect, if any, of atorvastatin alone or in combination with N-acetylcysteine in cecal ligaiton and perforation [CLP] model of sepsis in rats. Sixty four male albino rats weighing 150-200 g were used in the present study. Rats were randomly divided into eight groups, each of eight rats. Group I, sham operated group. Group II, non treated CLP control group. Group HI, vehicle-treated CLP control group, received saline SC and 2% gum acacia orally. Group IV, CLP group, treated by ceftriaxone plus gentamicin IM every six hours immediately after resuscitation. Group V, CLP group, treated by atorvastatin orally suspended in 2% gum acacia after resuscitation. Group VI, CLP group, treated by N-acetylcysteine [NAC] SC every 6 hours starting after resuscitation. Group VII, CLP group, treated by both atorvastatin and NAC in the same doses and routes of groups V and VI respectively. Group VIII, CLP group, treated by ceftriaxone-gentamicin combination as in group IV in addition to atorvastatin-NAC combination as in group VII. Twelve hours after CLP, malondialdehyde [MDA] levels, my eloperoxidase [MPO], superoxide dismutase [SOD], and catalase activities in heart, liver, and kidney were significantly elevated. Early treatment of CLP rats with ceftriaxone-gentamicin combination, atorvastatin and/or NAC caused a significant reduction in the aforementioned parameters. The concomitant administration of atorvastatin-NAC combination with ceftriaxone -gentamicin combined therapy nearly normalized the studied parameters. The results of the present work demonstrated that ROS plays an important role in CLP model of sepsis in rats. Furthermore, atorvastatin proved to have a protective effect in CLP rats which could be due to an antioxidant effect in addition to a possible anti-inflammatory action. These beneficial effects are augmented by the co-administration of NAC. Nevertheless, it is not advisable to use antioxidants alone for the management of sepsis, so it is recommended to use atorvastatin-NAC combination with optimum chemotherapeutic agents. Future human studies are indicated to assess the clinical relevance of the results of the present work in patients with septic shock

Study of the potential role of candesartan, selenium, or rosiglitazone in the amelioration of cyclosporine-induced nephrotoxicity in rats

The clinical utility of cyclosporine A [CsA] as an immunosuppressive agent has been significantly limited by the frequent occurrence of chronic nephropathy. This study was designed to investigate the possible role of candesartan or selenium in the amelioration of CsA-induced chronic nephropathy in rats. Furthermore, to delineate the possible, if any, modulatory role of rosiglitazone in this pathological status. Fifty male albino rats weighing 180-220 g were used in the present study. Rats were divided into five groups, each of ten rats. Group I, injected subcutaneously [SC] by olive oil and received also 2% gum acacia daily through a gastric tube. Group II injected with CsA SC daily for 6 weeks and received also 2% gum acacia orally daily for 6 weeks. Group III, IV, and V received the same dose of CsA concomitantly with candesartan, selenium, or rosiglitazone respectively through a gastric tube daily for 6 weeks. Administration of CsA to rats for six weeks resulted in significant high levels of plasma renin activity, serum urea, and creatinine. It also, caused a significant decrease in creatinine clearance, renal contents of glutathione [GSH], glutathione peroxidase [GPx], superoxide dismutase [SOD], catalase, and accompanied by high levels of malondialdehyde [MDA], proteinuria, and urinary N-acetyl-beta-D-glucosaminidase [NAG] activity. The histopathological studies revealed arteriolopathy and fibrosis. Concomitant administration of candesartan or rosiglitazone with CsA significantly reduced proteinuria and attenuated glomerulosclerosis. Also, they improved the renal function as evidenced by significantly lower concentrations of serum creatinine, serum urea, urinary NAG activity and improved natriuresis and creatinine clearance. These beneficial effects were accompanied by significant increase in renal contents of GSH, GPx, SOD, and catalase with reduced levels of MDA. Furthermore, concomitant administration of selenium with CsA significantly reduced proteinuria and glomerulosclerosis, improved creatinine clearance, and lowered concentrations of serum creatinine, urea nitrogen, and urinary NAG activity. Also, concomitant administration of selenium elevated GSH level, GPx activity, and reduced MDA level significantly. The results of the present study demonstrated that concomitant administration of candesartan, selenium, or rosiglitazone with CsA attenuates its structural and functional changes in a rat model of chronic CsA-induced nephropathy. Our findings provide a potential rationale for the use of candesartan or rosiglitazone alone or combined with selenium in future clinical studies

Inflammatory status in patients on chronic hemodialysis

All chronic renal failure patients show clinical and/or laboratory manifestations of inflammation. Prevalence of infection in chronic renal failure [CRF] patients is high due to immune dysfunction, also repeated cannulation and central venous catheters are probably responsible for the high incidence of infection. Detection of these pro-inflammatory cytokines in the plasma allow to detect patients with high risk of endotoxemia and also it was noticed that there is high degree of correlation between the inflammation, malnutrition and atherosclerotic process. The aim of the present study was to detect the level of plasma alpha-MSH as immunomodulator which counter acts the pro-inflammatory cytokines such as TNF-alpha, neopterin, nitric oxide [NO], C-reactive protein [CRP] and eridotoxins. This study was conducted on 40 subjects divided into three groups, 15 patients on maintenance hemodilaysis [GI], 15 patients with chronic renal failure not yet on dialysis [GII], and 10 healthy subjects as a control group [GIII]. Plasma alpha-MSH was measured using a double antibody radioimmunoassay, TNF-alpha and neopterin using specific enzyme-linked immunosorbent assays. Plasma nitrites were determined by a colorimetric method and endotoxin with the quantitative chromogenic method. The present study showed that most of the chronic renal failure patients show laboratory evidence of inflammation especially before starting dialysis. alpha-MSH was found to he elevated in both groups. Also, the levels of the proinflammatory cytokines, TNF-alpha, neopterin, nitric oxide, iNOS, C-reactive protein and plasma endotoxin were found to he elevated in both group I and group II. There was a positive correlation between alpha-MSH and endotoxemia. Also, there was a positive correlation between the level of endotoxins and the level of other pro-inflammatory cytokines suggesting the role of endotoxemia in stimulating the formation and release of the proinflammatory cytokines

Trace elements anti oxidant and streptozotocin-induced diabetes in rats

This study was conducted to delineate the possible therapeutic potential of chromium, lithium or selenium on glucose homeostasis, lipid profile and oxidative stress profile in streptozotocin-induced diabetes in rats treated by a subtherapeutic single daily dose of gliclazide [2mg/kg/day]. Therapeutic dose of gliclazide [10 mg/kg/day] produced a significant correction of the observed changes in serum glucose, serum C-peptide, liver glycogen, liver cholesterol, liver glutathione, lipid profile and oxidative stress parameters. On the other hand, subtherapeutic dose gliclazide [2 mg/kg/day] caused a significant decrease in serum glucose level, while the other studied parameters did not change. Lithium or selenium supplementation corrected the observed changes in liver glycogen, liver glutathione, lipid profile and the different oxidative stress parameters including glutathione peroxidase activity