Gehan H. Heeba

Gastroprotective effect of simvastatin against indomethacin-induced gastric ulcer in rats: Role of nitric oxide and prostaglandins

This study investigated the possible mechanisms underlying the gastroprotective effect of simvastatin against indomethacin-induced gastric ulcer in rats. Rats were randomly assigned to vehicle-, simvastatin-, simvastatin+L-arginine- and simvastatin+N(G)-nitro-L-arginine methyl ester (L-NAME)-pretreated groups for two weeks. Pyloric ligation was performed for the collection of gastric juice, and gastric ulceration was induced by a single intraperitoneal injection of indomethacin (30 mg/kg). Gastric juice parameters (total acid output, pepsin activity and mucin concentration) were determined. The stomachs tissues were used for determination of gastric mucosal lipid peroxides, superoxide dismutase, catalase, total nitrites and prostaglandin E(2) levels. Pretreatment with simvastatin (10 mg/kg, orally, for 2 weeks) caused significant reduction in gastric mucosal lesions and lipid peroxides associated with a significant increase in gastric juice mucin concentration. Simvastatin significantly increased the gastric mucosal total nitrite and prostaglandin E(2) levels. Additionally, simvastatin attenuated the elevations in gastric mucosal superoxide dismutase observed with indomethacin. The gastroprotective effect afforded by simvastatin was significantly augmented by coadministration with L-arginine (a nitric oxide precursor) and inhibited by coadministration with L-NAME (a nitric oxide synthase inhibitor). Results confirm a gastroprotective effect for simvastatin, and indicate that the anti-ulcer effect of simvastatin is mediated by scavenging free radicals, increasing nitric oxide and prostaglandin E(2) levels, and increasing gastric juice mucin production. We conclude that simvastatin represents a more suitable antihyperlipidemic therapy for patients who are at risk of gastric ulcers that were induced by the use of nonsteroidal anti-inflammatory drugs (NSAIDs).

Nebivolol regulates eNOS and iNOS expressions and alleviates oxidative stress in cerebral ischemia/reperfusion injury in rats

AIMS Oxidative stress-induced cell damage is reported to contribute to the pathogenesis of cerebral ischemia/reperfusion injury. This study investigated the neuroprotective effect of nebivolol against cerebral ischemia/reperfusion insult in rats. MAIN METHODS The model adopted was that of surgically-induced forebrain ischemia, performed by means of bilateral common carotid artery occlusion for 1h, followed by reperfusion for 24 h. The effects of 5 and 10 mg/kg nebivolol, treated for 7 days prior to ischemia/reperfusion insult, were investigated by estimating endothelial and inducible nitric oxide synthases (eNOS and iNOS) protein expressions and assessing oxidative stress-related biochemical parameters in the rat forebrain. Also, infarct volume measurement and histopathological study of the forebrain were examined. KEY FINDINGS Administration of nebivolol increased eNOS expression with simultaneous decrease in iNOS expression in a dose dependent manner. Moreover, nebivolol inhibited ischemia/reperfusion-induced depletion of reduced glutathione level and decreased the elevated total nitric oxide end production and malondialdehyde levels, superoxide dismutase and lactate dehydrogenase activities. A notable finding is that catalase activity was not changed in response to either ischemia/reperfusion insult or nebivolol treatment. However, the results confirmed that nebivolol significantly reduced infarct volume and alleviated ischemia/reperfusion-induced histopathological changes. SIGNIFICANCE The present study demonstrates the neuroprotective effect of nebivolol against cerebral ischemia/reperfusion insult. Neuroprotection observed with nebivolol may possibly be explained by regulating eNOS and iNOS expressions and by inhibition of oxidative stress-induced injury. Thus, nebivolol may be considered as a potential candidate for treatment in patients who are prone to stroke.

Effect of combined administration of ginger (Zingiber officinale Roscoe) and atorvastatin on the liver of rats.

Ginger is known to possess hypolipidemic, antioxidant and hepatoprotective properties. Combination therapy often takes advantage of complementary effects of different agents. This study investigated the combined effect of ginger extract (GE) and atorvastatin on lipid profile and on atorvastatin-induced hepatic injury. Rats were randomized into: control; GE (400 mg/kg); atorvastatin (20 mg/kg) alone or with GE or vitamin E, and atorvastatin (80 mg/kg) alone or with GE or vitamin E. Administration of 80 mg/kg atorvastatin for 4 weeks had major hepatotoxic effect whereas the lower dose (20 mg/kg) seems to cause mild liver injury. Besides lowering serum total cholesterol and hepatic superoxide dismutase (SOD) and catalase (CAT), atorvastatin significantly increased serum aminotransferases, hepatic malondialdehyde (MDA) and nitric oxide (NO). Concurrent administration of GE and atorvastatin had the opposite effect. Histopathological study revealed that GE reduced liver lesions induced by atorvastatin. The results indicate that the ability of ginger to lower serum cholesterol and to decrease aminotransferases, MDA and NO is clinically important, because its chronic administration will neither lead to side-effects nor to hepatic changes as occurs with high atorvastatin doses. Therefore, combination regimens containing GE and low dose of statins could be advantageous in treating hypercholesterolemic patients which are susceptible to liver function abnormalities.

Therapeutic potential of morin against liver fibrosis in rats: Modulation of oxidative stress, cytokine production and nuclear factor kappa B

Therapeutic potential of morin, a member of flavonoid family, against carbon tetrachloride (CCl4)-induced liver fibrosis in rats was investigated and compared with that of silymarin. Results show that treatment with morin (30 mg/kg/day) revealed attenuation in liver index and serum biomarkers of liver function that were enhanced by chronic CCl4 intoxication. Further, morin inhibited the elevated levels of malondialdehyde and nitric oxide and restored hepatic reduced glutathione to its normal level. The increased production of hepatic hydroxyproline content by CCl4 was markedly decreased by administration of morin. In addition, treatment with morin significantly attenuated the inflammatory responses caused by CCl4 as evident by the decreased hepatic tumor necrosis factor-alpha (TNF-α) level, immunohistochemical expressions of inducible nitric oxide synthase and nuclear factor kappa B. Collectively, this study indicates that morin possesses antifibrotic effect in the CCl4 model of fibrosis via reducing oxidative stress, inflammatory responses and fibrogenic markers.

Quercetin augments the protective effect of losartan against chronic doxorubicin cardiotoxicity in rats

The present study aimed to examine whether the co-administration of quercetin (QRN) and losartan (LOS) can produce additional protective effects against chronic DOX cardiotoxicity. Cardiotoxicity in rats was induced by intraperitoneal injection of doxorubicin (DOX) in a cumulative dose of 15mg/kg for two weeks. Results revealed that DOX administration exhibited elevated serum levels of TNF-α, creatine kinase (CK-MB), lactate dehydrogenase (LDH) in addition to increased myocardial lipid peroxide (MDA) and nitric oxide (NO) alongside attenuating cardiac antioxidant defense system of superoxide dismutase (SOD) and catalase (CAT) activities. DOX produced leukocyte infiltration and myocardial lesions. Pretreatment with QRN (10mg/kg, orally) solely or in combination with LOS (0.7mg/kg, orally) for 6 weeks markedly ameliorated all these biochemical characteristics, and substantially reduced the myocardium peroxidative damage. The protective effects obtained by LOS were more pronounced by its combination with QRN. Our results suggest that quercetin potentially augmented the cardioprotective effect of losartan against chronic DOX cardiotoxicity via its antioxidant and anti-inflammatory properties.

Rosuvastatin ameliorates diabetes-induced reproductive damage via suppression of oxidative stress, inflammatory and apoptotic pathways in male rats.

AIM Besides a cholesterol-lowering effect, rosuvastatin (RUV) possesses antioxidant and anti-inflammatory properties. The present study investigates the possible protective effects of RUV in diabetes-induced reproductive damage in rats. MAIN METHODS Diabetes was induced in male Wistar rats by injecting a single dose of streptozotocin (65mg/kg, i.p.). RUV in low and high doses (5 and 10mg/kg, p.o.) were administrated to diabetic rats for 8weeks. Reproductive damage was evaluated by estimation of testes and epididymis relative weights and caudal sperm count and motility in the control, untreated and RUV-treated diabetic rats. In addition, testicular malondialdehyde, reduced glutathione and nitric oxide levels, as well as, superoxide dismutase and myeloperoxidase activities were estimated. Finally, expressions of inflammatory [inducible nitric oxide synthase (iNOS) and nuclear factor-kappa B (NF-κB)] and apoptotic (caspase-3) markers besides histological examination of testicular tissues were performed. KEY FINDINGS Results showed that RUV improved sperm count and motility with decrease in testicular nitric oxide and malondialdehyde levels, as well as, myeloperoxidase activity and increase in reduced glutathione level and superoxide dismutase activity in diabetic rats. Further, RUV reduced testicular inflammation and cell death by decreasing the expressions of iNOS, NF-κB and caspase-3. SIGNIFICANCE Treatment with RUV protects against diabetes-induced testicular damage, in a dose dependent manner, through antioxidant, anti-inflammatory and anti-apoptotic mechanisms.

Comparative effects of Aliskiren and Telmisartan in high fructose diet-induced metabolic syndrome in rats

Fructose is a commonly used sweetener associated with diets that increase the prevalence of metabolic syndrome (MS). Inhibition of the renin-angiotensin system (RAS) has been consistently demonstrated to reduce MS. However, there has been no direct comparison among different pharmacological modes of inhibiting the RAS concerning their effects on MS. This study investigated the effect of aliskiren, a direct renin inhibitor, versus telmisartan, an angiotensin II-receptor blocker, in the treatment of fructose-induced MS in rats. MS was induced by high fructose (FRC) diet feeding for 12 weeks. Oral administrations of telmisartan (TEL, 5 mg/kg), aliskiren (ALS, 30 mg/kg) or vehicle were started in the last 4 weeks. Results showed that administration of either TEL or ALS with FRC diet equally ameliorated the metabolic parameters (glucose level, oral glucose tolerance test, insulin resistance and serum lipids profile), systolic blood pressure and oxidative stress markers (malondialdehyde, nitric oxide, reduced glutathione levels and catalase activity). Additionally, the effects of TEL and ALS were associated with a decrease in body composition index and attenuation of liver index, serum liver enzyme activities and hepatic expressions of inflammatory and fibrotic markers (tumor necrosis factor-α, nuclear factor kappa-B and transforming growth factor-β) with a significant increase in hepatic glucose transporter-2 and peroxisome proliferator-activated receptors-alpha and gamma expressions. The results suggested that, at indicated dosage, ALS has ameliorative effect equal to that of TEL against FRC-induced metabolic and hepatic disorders; implying that drugs which inhibit the RAS, by different mode of inhibition, profoundly affect fructose-induced MS in rats.

Fucoidan ameliorates steatohepatitis and insulin resistance by suppressing oxidative stress and inflammatory cytokines in experimental non-alcoholic fatty liver disease.

Fucoidan, a sulfated polysaccharide derived from brown seaweeds, possesses a wide range of pharmacological properties. In the present study, we investigated the therapeutic effect of fucoidan on non-alcoholic fatty liver disease (NAFLD) in rats. Rats were fed a high-fat diet (HFD) for 12 weeks to induce NAFLD. Oral administrations of fucoidan (100mg/kg, orally), metformin (200mg/kg, orally) or the vehicle were started in the last four weeks. Results showed that administration of fucoidan for 4 weeks attenuated the development of NAFLD as evidenced by the significant decrease in liver index, serum liver enzymes activities, serum total cholesterol and triglycerides, fasting serum glucose, insulin, insulin resistance, and body composition index. Further, fucoidan decreased hepatic malondialdehyde as well as nitric oxide concentrations, and concomitantly increased hepatic reduced glutathione level. In addition, the effect of fucoidan was accompanied with significant decrease in hepatic mRNA expressions of tumor necrosis factor-α, interleukins-1β and matrix metalloproteinase-2. Furthermore, histopathological examination confirmed the effect of fucoidan. In conclusion, fucoidan ameliorated the development of HFD-induced NAFLD in rats that may be, at least partly, related to its hypolipidemic, insulin sensitizing, antioxidant and anti-inflammatory mechanisms.

Anti-inflammatory potential of curcumin and quercetin in rats Role of oxidative stress, heme oxygenase-1 and TNF-α

Flavonoids are group of compounds that have been shown to possess potent anti-inflammatory effects in both cellular and animal models of inflammation. In the current study, the single and combined effects of the two flavonoids, curcumin and quercetin, against carrageenan-induced acute inflammation in rats were evaluated with emphasis on the role of oxidative stress, anti-inflammatory enzyme, heme oxygenase-1 (HO-1) and proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α). Curcumin (50 mg/kg), quercetin (50 mg/kg) and a combination of both were orally administered for 14 days before carrageenan injection in rats and compared with the reference nonsteroidal anti-inflammatory drug, indomethacin (10 mg/kg). The percentage increase in paw thickness was calculated. Frozen hind paws were used for the estimation of lipid peroxides (malondialdehyde, MDA), nitric oxide (NO), reduced glutathione (GSH), TNF-α level and HO-1 messenger RNA (mRNA) expression. Formalin-fixed hind paws were used for histopathological examination. Results showed that both curcumin and quercetin caused reduction in carrageenin-induced edema and lymphocytes infiltration along with the decrease is being even higher in case of their combination. Additionally, both flavonoids reduced MDA and NO formation, and restored GSH contents in the paw. Furthermore, both flavonoids increased HO-1 mRNA expression and decreased the elevated TNF-α level. Results showed that both flavonoids moderately lowered inflammation, while their combination was more effective. Accordingly, this study suggests that the reduction in oxidative stress and modulation of HO-1 mRNA expression and TNF-α release by curcumin and quercetin may contribute to the synergistic anti-inflammatory effects of these two flavonoids upon combination.

Dual effects of quercetin in doxorubicin-induced nephrotoxicity in rats and its modulation of the cytotoxic activity of doxorubicin on human carcinoma cells

Quercetin (QUR) has been shown to induce anti‐, as well as, pro‐oxidant effects depending on the dose and on the redox state of the cell. This study investigated the effects of different doses of QUR on doxorubicin (DOX)‐induced nephrotoxicity in rats with emphasis on the suggested mechanisms and its modulation of the cytotoxic activity of DOX on different human carcinoma cell lines. Three doses of QUR (10, 50, and 100 mg kg−1) were administered orally to adult male albino rats for 14 days, in the presence or absence of nephrotoxicity induced by a single intraperitoneal injection of DOX (15 mg kg−1) at day 7 of the experiment. Moreover, the effect of QUR in the presence of DOX on the cell viability of four different human cancer cell lines; PC3, HELA, MCF7, and HEPG2 was studied. Results showed that the lowest dose of QUR was more effective in preserving renal function (kidney index, blood urea nitrogen, serum creatinine, renal malondialdehyde, nitric oxide, reduced glutathione, catalase activity, renal expressions of TNF‐α, IL‐1B, iNOS, and caspase‐3, and renal histopathology) than higher doses. Alternatively, the pro‐oxidant and pro‐inflammatory mechanisms have been reflected at highest QUR dose. In conclusion, QUR protected against DOX‐induced nephrotoxicity with a provision to dosage adjustment. Furthermore, QUR did not interfere but rather enhanced the cytotoxic effects of DOX on different human cancer cell lines.