Aly M. Abdelrahman

Involvement of the nitric oxide/L-arginine and sympathetic nervous systems on the vasodepressor action of human urotensin II in anesthetized rats

This study examined if the nitric oxide (NO)/L-arginine pathway participates in and if the sympathetic nervous system attenuates the depressor action of human urotensin II. I.V. bolus injections of human urotensin II (0.1-30 nmol/kg) caused dose-dependent decreases in mean arterial pressure (MAP, EC(50) = 2.09 +/- 0.8 nmol/kg; Emax = -18 +/- 3 mmHg ) and increases in heart rate. The depressor response to human urotensin II (3 nmol/kg) was attenuated by approximately 50% in rats with MAP elevated through pretreatment with N(G)-nitro-L-arginine methyl ester (inhibitor of NO synthase), relative to that in rats with MAP elevated to a similar level through a continuous infusion of noradrenaline. Autonomic blockade with i.v. injections of mecamylamine (ganglion blocker) and propranolol (beta-adrenoceptor antagonist) markedly augmented the depressor response to human urotensin II, but almost completely attenuated the tachycardia. The results suggest that the depressor response to human urotensin II is partially mediated via the NO/L-arginine pathway, and is suppressed by activity of the sympathetic nervous system. Furthermore, tachycardic response to human urotensin II is primarily mediated indirectly via baroreflex mechanisms.

Effect of coenzyme-Q10 on doxorubicin-induced nephrotoxicity in rats

Nephrotoxicity is one of the limiting factors for using doxorubicin (Dox) as an anticancer chemotherapeutic. Here, we investigated possible protective effect of coenzyme-Q10 (CoQ10) on Dox-induced nephrotoxicity and the mechanisms involved. Two doses (10 and 100u2009mg/kg) of CoQ10 were administered orally to rats for 8 days, in the presence or absence of nephrotoxicity induced by a single intraperitoneal injection of Dox (15u2009mg/kg) at day 4 of the experiment. Our results showed that the low dose of CoQ10 succeeded in reversing Dox-induced nephrotoxicity to control levels (e.g., levels of blood urea nitrogen and serum creatinine, concentrations of renal reduced glutathione (GSH) and malondialdehyde, catalase activity and caspase 3 expression, and renal histopathology). Alternatively, the high dose of CoQ10 showed no superior nephroprotection over the low dose, as there were no significant improvements in renal histopathology, catalase activity, or caspase 3 expression compared to the Dox-treated group. Interestingly, the high dose of CoQ10 alone significantly decreased renal GSH level as well as catalase activity and caused a mild induction of caspase 3 expression compared to control, probably due to a prooxidant effect at this dose of CoQ10. We conclude that CoQ10 protects from Dox-induced nephrotoxicity with a precaution to dosage adjustment.

Protective effect of peroxisome proliferator activator receptor (PPAR)-α and -γ ligands against methotrexate-induced nephrotoxicity

Abstract Context: The anticancer drug methotrexate (MTX) may cause multi-organ toxicities, including nephrotoxicity. Objective: To investigate effects of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists; fenofibrate (FEN) and pioglitazone (PIO), in MTX-induced nephrotoxicity in rats. Methods: Rats were given FEN or PIO (150 or 5u2009mg/kg/day, respectively) orally for 15 days. MTX was injected as a single dose of 20u2009mg/kg, i.p. at day 11 of experiment, with or without either PPAR agonists. Results: MTX induced renal toxicity, assessed by increase in serum urea and creatinine as well as histopathological alterations. MTX caused renal oxidative/nitrosative stress, indicated by decrease in GSH and catalase with increase in malondialdehyde and nitric oxide (NOx) levels. In addition, MTX increased renal level of the pro-inflammatory cytokine; tumor necrosis factor (TNF)-α and up-regulated the expression of both the inflammatory and apoptotic markers; NF-κB and caspase 3. Pre-administration of FEN or PIO to MTX-treated rats improved renal function and reversed oxidative/nitrosative parameters. Interestingly, pre-administration of PIO, but not FEN, decreased renal TNF-α level and NF-κB expression compared to MTX alone. Furthermore, PIO had more significant effect than FEN on reversing MTX-induced renal caspase 3 expression. Discussion: Both FEN and PIO conferred protection against MTX-induced nephrotoxicity through comparable amelioration of oxidative/nitrosative stress. FEN lacked any effect on TNF-α/NF-κB, which was reflected on its less improvement on renal histopathology and apoptosis. Conclusion: At indicated dosage, PPAR-γ ligand; PIO shows better improvement of MTX-induced nephrotoxicity compared to PPAR-α ligand; FEN due to differential effect on TNF-α/NF-κB inflammatory pathway.

Effect of Metformin and Sitagliptin on Doxorubicin-Induced Cardiotoxicity in Rats: Impact of Oxidative Stress, Inflammation, and Apoptosis

Doxorubicin (DOX) is a widely used antineoplastic drug whose efficacy is limited by its cardiotoxicity. The aim of this study was to investigate the possible protective role of the antidiabetic drugs metformin (250u2009mg/kg dissolved in DW p.o. for seven days) and sitagliptin (10u2009mg/kg dissolved in DW p.o. for seven days) in a model of DOX-induced (single dose 15u2009mg/kg i.p. at the fifth day) cardiotoxicity in rats. Results of our study revealed that pretreatment with metformin or sitagliptin produced significant (P < 0.05) cardiac protection manifested by a significant decrease in serum levels of LDH and CK-MB enzymes and cardiac MDA and total nitrites and nitrates levels, a significant increase in cardiac SOD activity, and remarkable improvement in the histopathological features as well as a significant reduction in the immunohistochemical expression of COX-2, iNOS, and caspase-3 enzymes as compared to DOX group. These results may suggest using metformin and/or sitagliptin as preferable drugs for diabetic patients suffering from cancer and receiving DOX in their chemotherapy regimen.

Montelukast and irbesartan ameliorate metabolic and hepatic disorders in fructose-induced metabolic syndrome in rats

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.

Molecular mechanisms contributing to the protective effect of levosimendan in liver ischemia-reperfusion injury

Ischemia-reperfusion injury (IRI) is an important cause of liver damage in many clinical situations. Levosimendan is a promising therapy for prevention of IRI. The present work investigated the possible contribution of nitric oxide (NO), cyclooxygenase (COX) enzymes, and adenosine triphosphate sensitive potassium channel (K-ATP) in the protective effect of levosimendan in liver IRI in rats. Rats were divided into 7 groups. Sham-operated group (negative control group); IR-nontreated group (positive control group), levosimendan-treated group (treated with levosimendan); indomethacin, nonselective COX inhibitor,+levosimendan group (cotreated with indomethacin+levosimendan); celecoxib (selective COX-2 inhibitor)+levosimendan group; L-NNA (Nitro- ω-L-arginine, nonselective NO synthase inhibitor)+levosimendan group; and glibenclamide (K-ATP blocker)+levosimendan group. Liver injury was evaluated biochemically (by serum level of alanine aminotransferase (ALT)) as well as by histopathology. Hepatic tissue content of oxidative stress markers, tumor necrosis factor-alpha (TNF-α), along with immunohistochemical expression of induced NO synthase (iNOS), endothelial NO synthase (eNOS), and caspase-3 in hepatic tissue were assayed. The study showed that levosimendan attenuated liver IRI as evidenced by a decrease in serum ALT level and confirmed by histopathology. The protective effect of levosimendan was associated with modulation of oxidative stress, TNF-α, iNOS, eNOS, and caspase-3. The hepatoprotective effect of levosimendan was partially attenuated by pretreatment by either nonselective COX inhibitor, NOS inhibitor, or K-ATP channel blocker; indicating that the hepatoprotective effect of levosimendan was attributed, at least in part to activation of COX-1, modulation of NO, and opening of K-ATP channel.

Possible Protective Effect of Diacerein on Doxorubicin-Induced Nephrotoxicity in Rats

Nephrotoxicity is one of the limiting factors for using doxorubicin (DOX). Interleukin 1 has major role in DOX-induced nephrotoxicity, so we investigated the effect of interleukin 1 receptor antagonist diacerein (DIA) on DOX-induced nephrotoxicity. DIA (25 and 50u2009mg/kg/day) was administered orally to rats for 15 days, in the presence or absence of nephrotoxicity induced by a single intraperitoneal injection of DOX (15u2009mg/kg) at the 11th day. We measured levels of serum urea, creatinine, renal reduced glutathione (GSH), malondialdehyde (MDA), total nitrites (NOx), catalase, and superoxide dismutase (SOD). In addition, caspase-3, tumor necrosis factor alpha (TNFα), nuclear factor kappa B (NFκB) expressions, and renal histopathology were assessed. Our results showed that DOX-induced nephrotoxicity was ameliorated or reduced by both doses of DIA, but diacerein high dose (DHD) showed more improvement than diacerein low dose (DLD). This protective effect was manifested by significant improvement in all measured parameters compared to DOX treated group by using DHD. DLD showed significant improvement of creatinine, MDA, NOx, GSH, histopathology, and immunohistochemical parameters compared to DOX treated group.

Potential protective effect of etanercept and aminoguanidine in methotrexate-induced hepatotoxicity and nephrotoxicity in rats.

Methotrexate (MTX), a chemotherapeutic and immunosuppressant drug, is generally well-tolerated by most patients. However, its cytotoxic nature contributes to life-threatening side effects including hepatotoxicity and nephrotoxicity. The present study investigated the possible role of tumor necrosis factor-alpha (TNF-α) inhibitor, etanercept and inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine, on MTX-induced hepatotoxicity and nephrotoxicity in rats. Rats were divided into 7 groups: control group, etanercept group, aminoguanidine group, MTX group, MTX+etanercept group, MTX+aminoguanidine group, and MTX+etanercept+aminoguanidine group. MTX caused hepatotoxicity and nephrotoxicity as evidenced biochemically by significant increase in serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea and creatinine, respectively as well as by histopathological changes. Such effects were associated with significant changes in oxidative stress markers (malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), catalase, and glutathione (GSH)) as well as by upregulation of TNF-α, iNOS and caspase-3 expressions in hepatic and renal tissues. Etanercept and aminoguanidine significantly attenuated MTX-hepatotoxicity and nephrotoxicity. The protective effect of either agent was associated with significant improvement in oxidative stress parameters as well as by downregulation of TNF-α, iNOS and caspase-3 expressions in hepatic and renal tissues. The study suggested that inhibitors of either TNF-α and/or iNOS have protective effect in MTX-induced hepatotoxicity and nephrotoxicity. The protective effect of either agent relies, at least partially, on their antioxidant effects and decreased TNF-α, iNOS, and caspase-3 expressions.

Nitro-aspirin is a potential therapy for non alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver injury; however its therapeutic strategy has not been established yet. Nitro-aspirin (NO-aspirin) is a new molecule in which aspirin and a NO-donating group are covalently linked. This study investigated the potential protective effect of NO-aspirin on NAFLD. Experimental rats were assigned into 4 groups. Group 1 was fed with normal diet and served as normal control group. Group 2 was fed with 2% cholesterol diet and received vehicle as positive control NAFLD group. Group 3 was fed with 2% cholesterol diet plus NO-aspirin (100 mg/kg/day). Group 4 was fed with 2% cholesterol diet plus aspirin (55 mg/kg/day). Rats were treated for 8 weeks. The results showed that NO-aspirin (but not aspirin) prevented the development of NAFLD as evidenced by significant reduction in liver weight/body weight ratio (liver index) and histopathologic changes. The protective effect of NO-aspirin is accompanied with significant decrease in triglycerides, malondialdehyde (MDA), and nitric oxide (NO) in hepatic tissue. Semi-quantitative immunohistochemical studies showed significant decrease in expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in hepatic tissue. In conclusion, NO-aspirin inhibited multiple pathways involved in the pathogenesis of NAFLD indicating that it might serve as a new therapeutic strategy.

Effect of captopril and telmisartan on methotrexate-induced hepatotoxicity in rats: impact of oxidative stress, inflammation and apoptosis.

Abstract Methotrexate (MTX) is a commonly used antineoplastic and anti-rheumatoid drug whose efficacy is limited by its hepatotoxicity. The aim of this study was to investigate the possible protective role of captopril (100u2009mg/kg/day, p.o. for seven days), an angiotensin converting enzyme inhibitor, and telmisartan (10u2009mg/kg/day p.o. for seven days), an angiotensin II receptor blocker with peroxisome proliferative receptor gamma (PPARγ) agonism, in a model of MTX (single dose 20u2009mg/kg i.p. at the fifth day) induced hepatotoxicity in rats. Results of the present study revealed MTX-induced hepatotoxicity as demonstrated by increased level of liver enzymes and confirmed by histopathology. Pretreatment with captopril or telmisartan produced a significant hepatic protection manifested as a significant (pu2009<u20090.05) decrease in serum levels of alanine transferase (ALT) and aspartate transferase (AST) and alkaline phosphatase (ALP) enzymes; hepatic malondialdehyde (MDA) and total nitrites and nitrates (NOx) levels; as well as a significant increase in hepatic superoxide dismutase (SOD) activity. In addition, there was a remarkable improvement in the histopathological features and a significant reduction in the expression of COX-2, iNOS and caspase-3 enzymes as compared with the MTX group. We recommend considering captopril/Telmisartan, if tolerated and not contraindicated, as preferable antihypertensive agents in patients receiving MTX in their chemotherapy protocols.