montelukast and Liver-Diseases

Metabolic syndrome (MetS) is a global health problem. Elucidation of the role of 5- lipooxygenase/leukotriene pathway and renin angiotensin system in the pathogenesis of MetS suggests a variety of potential therapies worthy of testing. The present work investigated the effect of montelukast, a leukotriene antagonist and/or irbesartan, an angiotensin II-receptor blocker, in the prevention of fructose-induced MetS in rats. Rats were allocated into 9 groups and treated for 6 weeks as follow: normal control; MetS group (received 20% fructose); MetS+montelukast groups (treated with montelukast, 5, 10, and 20 mg/kg/day, respectively); MetS+irbesartan groups (treated withirbesartan 15, 30, and 45 mg/kg/day, respectively); and MetS+montelukast+irbesartan group (co treated with montelukast 5 mg/kg plus irbesartan 15 mg/g). Metabolic parameters (visceral fat index, liver index, insulin resistance, and serum lipid profile), oxidative stress markers (malondialdehyde, reduced glutathione, and catalase), and inflammatory mediators (tumor necrosis factor-α, and uric acid) were measured. Expression of caspase-3 in hepatic tissues was detected by immunohistochemistry. Liver injury was evaluated by histopathological examination and serum alanine aminotransferase (ALT). Montelukast, irbesartan, and their combination caused significant attenuation in metabolic and hepatic disorders. Their effect was associated with attenuation of oxidative stress markers, inflammatory mediators, and caspase-3 expression. This study highlighted the protective effects of montelukast and irbesartan against fructose-induced metabolic and hepatic disorders. The protective effect of either drug relies, at least in part, on their antioxidant and antiinflammatory effect, as well as on the reduction of caspase-3 expression in hepatic tissue.

Topics: Acetates; Alanine Transaminase; Angiotensin II Type 1 Receptor Blockers; Animals; Biphenyl Compounds; Blood Glucose; Caspase 3; Cyclopropanes; Fructose; Insulin; Irbesartan; Leukotriene Antagonists; Lipids; Liver; Liver Diseases; Male; Metabolic Syndrome; Quinolines; Rats; Rats, Wistar; Sulfides; Tetrazoles

Ischemia and reperfusion (I/R) injury is characterized by significant oxidative stress, characteristic changes in the antioxidant system and organ injury leading to significant morbidity and mortality. This study was designed to assess the possible protective effect of montelukast, a selective antagonist of cysteinyl leukotriene receptor 1 (CysLT1), on hepatic I/R injury in rats. Wistar albino rats through clamping hepatic artery, portal vein, and bile duct, were subjected to 45 min of hepatic ischemia followed by 60 min reperfusion period. Montelukast (10 mg/kg; i.p.) was administered 15 min prior to ischemia and immediately before reperfusion period. At the end of the reperfusion period, the rats were killed by decapitation. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) activity, and proinflammatory cytokines (TNF-alpha and IL-1beta) were determined in blood samples. Malondialdehyde (MDA), and glutathione (GSH) levels and myeloperoxidase (MPO) and Na+, K+-ATPase activities were determined in the liver tissue samples while formation of reactive oxygen species was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes. Tissues were also analyzed histologically. Serum ALT, AST, and LDH activities were elevated in the I/R group, while this increase was significantly decreased by montelukast treatment. Hepatic GSH levels and Na+, K+-ATPase activity, significantly depressed by I/R, were elevated back to control levels in montelukast-treated I/R group. Furthermore, increases in tissue luminol and lucigenin CL, MDA levels, and MPO activity due to I/R injury were reduced back to control levels with montelukast treatment. Since montelukast administration alleviated the I/R-induced liver injury and improved the hepatic structure and function, it seems likely that montelukast with its anti-inflammatory and antioxidant properties may be of potential therapeutic value in protecting the liver against oxidative injury due to ischemia-reperfusion.

Topics: Acetates; Animals; Cyclopropanes; Cytokines; Glutathione; Leukotriene Antagonists; Liver; Liver Diseases; Liver Function Tests; Male; Malondialdehyde; Peroxidase; Quinolines; Rats; Rats, Wistar; Reperfusion Injury; Sulfides

Hepatic ischemia-reperfusion injury (I/R) may occur in transplantation, trauma, and elective hepatic resections. Leukotrienes have been shown to play a major role in hepatic I/R injury. Five-lipoxygenase enzyme is an important enzyme in the production of leukotrienes from arachidonic acid. MK-886 is an inhibitor of 5-lipoxygenase, and montelukast is a cysteinyl leukotriene receptor antagonist. The aim of this study was to investigate whether MK-886 and montelukast are effective in preventing hepatic I/R injury.. Rats were divided into five groups consisting of seven rats in each: (1) Control I/R, (2) Control-montelukast, (3) Control-MK-886, (4) I/R+montelukast, and (5) I/R+MK-886. Thirty min of total hepatic vascular occlusion and then 60 min reperfusion were performed to animals in groups 1, 4, and 5. In groups 2 and 4, montelukast, and in groups 3 and 5, MK-886 was applied intraperitoneally before and during the surgical procedures.. Apoptosis in the liver and intestine decreased significantly in the I/R+montelukast and I/R+MK-886 groups compared with the I/R group. Tissue malondialdehyde levels and glutathione consumptions also decreased significantly in the I/R+montelukast and I/R+MK-886 groups compared with the I/R group. The difference in serum alanine aminotransferase and aspartate aminotransferase levels between the groups did not reach significance.. Montelukast and MK-886 were found to be effective in prevention of liver and intestine injury by reducing apoptosis and oxidative stress in a hepatic I/R model. Anti-inflammatory properties and inhibition of lipid peroxidation by montelukast and MK-886 could be protective for these organs in I/R injury.

Topics: Acetates; Animals; Cyclopropanes; Disease Models, Animal; Indoles; Leukotriene Antagonists; Lipoxygenase Inhibitors; Liver Diseases; Male; Quinolines; Rats; Rats, Wistar; Reperfusion Injury; Sulfides

This study investigates the effects of montelukast sodium (MK) (CysLTLT1 receptor antagonist) on CCl(4)induced hepatopathy on rat.. We worked on 4 groups of 10 Wistar male rats each. The groups received as follows: group I (control group) - saline, group II - MK 5mg/kg/day i.p. for 5 days, group III - MK 5mg/kg/day i.p., 1 day prior to and 4 days concomitantly with CCl(4) p.o., 0.3ml/Kg/day and group IV - CCl(4), p.o., 0.3ml/Kg/day for 4 days. One day after the last administration, samples of blood were taken and alanine aminotransferase (ALT), total bilirubin (TB), direct bilirubin (DB), malondialdehyde (MDA), catalase (CAT) as well as total antioxidant capacity (TAC) were determined. The histopathological exam was performed. We also determined superoxide dismutase (SOD), MDA, CAT and GSH in liver homogenate.. Compared to group IV, group III exhibited statistically significant lower levels of ALT (318+/-15.75 versus 203.14+/-10.28 UI, p<0.0001), TB (3.16+/-0.30 versus 1.99+/-0.08mg/dl, p<0.0001), MDA in blood and in liver homogenate (4.98+/-1.71 versus 2.15+/-1.18nmol/ml, p=0.0004) and higher levels of SOD and CAT. Histopathologically, group IV presented important macro- and micro-vesicular hepatic steatosis and group III preserved lobular histoarchitecture and had less severe cellular lesions.. MK exhibits a partial hepatoprotective effect on rats treated with CCl(4).

Topics: Acetates; Alanine Transaminase; Animals; Bilirubin; Carbon Tetrachloride; Catalase; Chemical and Drug Induced Liver Injury; Cyclopropanes; Liver; Liver Diseases; Male; Malondialdehyde; Quinolines; Rats; Rats, Wistar; Sulfides; Superoxide Dismutase

Sepsis is a generalized inflammatory response, which involves organ systems remote from the locus of the initial infectious insult, involves the release of cytokines and the subsequent formation of reactive oxygen and nitrogen species.. The aim of this study was to investigate the possible protective effect of montelukast, a leukotriene receptor blocker, against oxidative damage in the liver and ileum of septic rats.. Sepsis was induced by cecal ligation and puncture method in female Wistar albino rats. Sepsis and sham operated (control) groups received either saline or montelukast (10 mg/kg, ip) immediately after the operation and at 12 h. Twenty-four hours after the surgery, rats were decapitated and malondialdehyde (MDA) content--an index of lipid peroxidation, glutathione (GSH) levels--a key antioxidant, myeloperoxidase (MPO) activity--an index of neutrophil infiltration, and collagen contents were determined in the liver and ileum. Formation of reactive oxygen species in liver and ileal tissue samples was monitored by using chemiluminescence (CL) technique with luminol and lucigenin probes. Both tissues were also analyzed histologically. Serum lactate dehydrogenase (LDH) and tumor necrosis factor-alpha (TNF-alpha) level were assessed in trunk blood.. Sepsis resulted in decreased GSH levels, and increased MDA levels, MPO activity, CL levels and collagen contents in both the liver and the ileum (P < 0.05-P < 0.001) indicating the presence of the oxidative damage. Similarly, serum TNF-alpha and LDH were elevated in the sepsis group as compared to control group. On the other hand, montelukast treatment reversed all these biochemical indices, as well as histopathological alterations, which were induced by sepsis.. Findings of the present study suggest that montelukast possesses an anti-inflammatory effect on sepsis-induced hepatic and intestinal damage and protects against oxidative injury by a neutrophil-dependent mechanism.

Topics: Acetates; Animals; Cecum; Collagen; Cyclopropanes; Glutathione; Ileal Diseases; Ileum; L-Lactate Dehydrogenase; Leukotriene Antagonists; Ligation; Liver; Liver Diseases; Luminescent Measurements; Malondialdehyde; Peroxidase; Quinolines; Rats; Rats, Wistar; Sepsis; Sulfides; Tumor Necrosis Factor-alpha