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

Protection against acute adriamycin-induced cardiotoxicity by nigella sativa oil, thymoquinone, garlic extract and COQ[10] in rats

Oxidative stress is a major etiologic factor in adriamycin [ADR]-induced cardiotoxicity that limits the clinical efficacy of this anticancer drug. Since, many beneficial health-related biological properties are attributed to Nigella sativa L. oil [NSO], thymoquinone [TQ], garlic, and Coenzyme Q-10, the present study examined the cardioprotective effect of these remedies against ADR-induced cardiotoxicity. The study was carried out on 110 male Albino rats. They were divided into a control group [10 rats] and 5 groups of ADR-treated rats [n=20 in each] as follows: [i] ADR, [ii] CoQ10+ADR [iii] NSO+ADR [iv] Garlic+ADR and [v] TQ+ADR groups. Administration of CoQ10, NSO, garlic, and TQ were started one week prior to ADR and continued once daily thereafter for the next 2 weeks. The assessment of cardiac affection was carried out by measuring the level of serum creatine kinase [CK] and lactate dehydrogenase [LDH]. Also, activities of superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPX], cytosolic aconitase [c-aconitase] as well as the malondialdehyde [MDA] and cell iron content were measured in myocardial tissue homogenate. Moreover, light and electron microscopic changes were scored. The administration of ADR to the experimental rats produced wide range of changes. A significant decrease in activities of the antioxidant enzymes SOD, CAT and GPX in ADR-treated rats was found compared to normal control values. Also, myocardial MDA level was significantly high as well as serum LDH and CK denoting myocardial injury. The ADR-treated rats also showed significant inhibition of myocardial c-aconitase activity and rise of cell iron content compared to control myocardium. The histological results of this group revealed hypereosinophilia, myofibrillar damage, nuclear abnormalities, mitochondrial degeneration and diminished glycogen. Neither CoQ10 nor the whole oil of nigella sativa significantly modified ADR-induced impairment in SOD, GPX or CAT activity. CK was significantly less elevated in the NSO but insignificantly different in the CoQ10 while LDH was significantly less elevated in both groups compared to ADR group. Activity of c-aconitase was significantly higher in NSO than CoQ10 and ADR groups while cellular iron was insignificantly different. Also, survival was significantly improved in the NSO but not in the CoQ10 compared to ADR group. These findings were further documented by the histological findings. Examination of ADR-CoQ[10] treated rats showed extensive cellular damage including the mitochondria, intercalated discs, the cytoskeleton, the nuclei and diminished glycogen deposition. Conversely, 3 weeks administration of TQ and garlic in the present study have yielded encouraging results against acute ADR-induced cardiotoxicity in rats, as indicated by 100% survival rate which was found in these groups versus 40-50% in the ADR and CoQ10 treated groups. Moreover, they have been associated with: conserved activity of myocardial antioxidant enzymes GPX, SOD and CAT with suppression of MDA formation and less accumulation of cellular iron compared to ADR, CoQ10 and NSO treated groups. The histological results further proved this results and revealed high degree of myocardial protection in TQ-treated rats and garlic-treated rats respectively where the most examined myocytes were nearly normal. Thymoquinone [TQ] and garlic had shown significant cardioprotective effect much superior to NSO and CoQ10 against ADR-induced myocardial toxicity. The low TQ content in the chosen dose of NSO could be the underlying cause of lacking therapeutic effect although a strong antioxidant effect have been recently reported with this dose of NSO. Hence, a larger dose of NSO and probably of CoQ10 can be subjected to further study for protection against ADR-induced cardiac injury

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

Probing the possible interaction between montelukast or rosiglitazone and combined bisphosphonate-NSAIDs therapy on rat stomach

Gastric ulceration associated with the use of nonsteroidal anti-inflammatory drugs [NSAIDs] is mostly observed in elderly women, the same sector of society most likely to be receiving therapy for osteoporosis. Alendronate sodium, an aminobisphosphonate, is a selective inhibitor of osteoclast-mediated bone resorption. It is used for treatment and prevention of postmenopausal osteoporosis. It can cause irritation and inflammation of the upper gastrointestinal mucosa. This study was designed to delineate the effects of combined alendronate-indomethacin therapy on gastric mucosa of rats and the possible modulatory effects of montelukast or rosiglitazone. Fifty six adult male albino rats weighing 200-250g were used in this study and divided into seven groups, each of eight animals as follows: group I used as control untreated animals and received 1 ml of 0.9% saline, the vehicle, orally daily for six days, group II used as control treated animals and received alendronate only, group III used as control treated animals and received alendronate combined with indomethacin, group IV received montelukast before alendronate administration, group V received montelukast before combined administration of alendronate-indomethacin, group VI received rosiglitazone before alendronate administration, and group VII received rosiglitazone before combined administration of alendronate and indomethacin. Alendronate treatment produced a significant increase in gastric acidity, ulcer index, gastric myeloperoxidase [MPO] activity and malondialdehyde [MDA] levels in the stomach accompanied by a significant reduction in glutathione levels. The combined alendronate-indomethacin administration produced further significant deleterious changes on the previous studied parameters when compared with the alendronate-treated group. The previous changes in biochemical parameters were accompanied by histopathological changes evidenced by epithelial ulceration, dilatation of gastric glands, and infiltration by inflammatory cells. The gastric mucosal damage was more pronounced by the combined use of alendronate with indomethacin. Montelukast or rosiglitazone therapy produced a significant reduction in gastric acidity, ulcer index, gastric MPO activity, and MDA levels in the stomach accompanied by a significant increase in glutathione levels, both in alendronate-treated group and in alendronate-indomethacin combined group. Moreover, both drugs reduced the histopathological changes. The results of the present study demonstrated that alendronate-indomethacin combined therapy induced gastric damage more significant than alendronate alone and that the use of either montelukast or rosiglitazone can reduce these hazardous effects in rat gastric mucosa. Further studies on humans are needed to evaluate the clinical use of the studied drugs in patients using alendronate alone or in combination with NSAIDs

study of the potential role of aldose reductase inhibitors [Sorbinil, Tolrestat and Ponalrestat] in the amelioration of nephropathy in diabetic rats

This work included 90 male albino rats. Diabetes was induced by a single intraperitoneal injection of streptozotocin [STZ] in a dose of 55 mg/kg body weight. One week after STZ injection, uninephrectomy was done and the study began one week after uninephrectomy operation and continued for eight months. The results revealed that oral administration of sorbinil, tolrestat or ponalrestat for eight months in uninephrectomized [UNE] diabetic rats produced significant decreases in sorbitol and fructose levels in RBCs, kidney sorbitol and aldose reductase activity in RBCs associated with significant increases in Na

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

Beta-blockers and renal ablated rats

This study was conducted to compare the effects of carvedilol, celiprolol and propranolol on some renal function parameters, oxidative stress profile and histopathological features in renal ablated rats and to evaluate the effects of supplementation of celiprolol or propranolol treatment with vitamin E on the previously mentioned parameters. It was concluded that vasodilator beta-blockers with antioxidant activity as carvedilol offered renoprotective effects more than propranolol. Carvedilol exhibited an increasing histopathological and functional end-organ protection in renal ablated rats. The reduction of plasma renin activity and lipid peroxidation may contribute to its renoprotective effects. The addition of vitamin E to celiprolol or propranolol treatment was mandatory to improve renal function and lipid peroxidation in partially ablated rats

possible protective effect of some drugs on hepatic ischemia / reperfusion injury

This work aimed to clarify the possible protective effect of verapamil, allopurinol, dimethyl sulfoxide [DMSO], N-acetylcysteine [NAC], pentoxifylline [PTX] on hepatic injury induced by acute ischemia, followed by reperfusion in normal rats and rats sensitized to oxidative injury by depletion of endogenous glutathione. 84 male rats were randomized into seven groups. One served as a control group and the other groups were treated either with vehicle or with one of the previously mentioned drugs prior to induction of ischemia. The present study showed that ischemia/reperfusion [IR] significantly decreased hepatic glutathione [GSH] in both normal and GSH-depleted rat groups. All the tested drugs significantly prevented this reduction in both groups. Ischemia/reperfusion injury significantly increased hepatic malonyldialdehyde [MDA] level only in GSH-depleted rats. Hepatic myeloperoxidase [MPO] activity was significantly increased both in normal and GSH-depleted rats subjected to ischemia/reperfusion injury. Pretreatment with PTX significantly prevented this increase in hepatic MPO activity. Other tested drugs could not exert any protective effect