Carnosine protects against gentamicin-induced nephrotoxicity in rats

Acute renal failure is a major complication of gentamicin, limiting use of this antibiotic in treatment of gram negative infections. Reactive oxygen species are hypothesized to be a major factor in the nephrotoxicity of gentamicin and measures controlling this oxidative damage are widely appreciated. This work was conducted to test the hypothesis that treatment with carnosine, a biological antioxidant, may prevent or ameliorate acute renal injury, using a rat model of gentamicin-induced nephrotoxicity. Male wistar albino rats were assigned to one of six treatment groups; group I [control] rats were given normal saline injections daily for 10 days; group II rats were given IM gentamicin injections, 100 mg/kg/day, for 6 days: group III, IV and V rats were given gentamicin, together with IP carnosine injections 50, 100 and 200 mg/kg/day, respectively, for 10 days starting 4 days before gentamicin injections; and group VI rats were given only carnosine 200 mg/kg/day, for 10 days. All rats were weighed before and after experimentation, and 24 hour urine volume were collected in metabolic cages. At end of study, blood samples were collected for measurement of BUN, creatinine level and creatinine clearance. Rats were then sacrificed and the kidneys were excised. The left kidneys were homogenized and used for biochemical determination of MDA, GPX and SOD, while the right kidneys were processed for histological examination and scoring of renal cortical pathology. Results showed that gentamicin produced evident nephrotoxic effects revealed by; increased kidney weight, increased urine volume, elevations of serum levels of BUN and creatinine and decreased creatinine clearance; together with increased MDA, reduced GPX and SOD in kidney tissues. Marked histological alterations were also evident in the renal cortex [acute tubular necrosis of grade 2-3]. Carnosine treatment leads to significant dose-related attenuation of nephrotoxic effects of gentamicin revealed by reduction of the elevated biochemical parameters, improved oxidative status in the kidney, and amelioration of the histological changes. It is concluded that carnosine treatment could ameliorate the severity of renal cortical necrosis induced by gentamicin and maintain a better renal function. Thus, carnosine may be a useful candidate in the combination therapy with gentamicin to limit free radical-mediated renal injury

Evidence of Prothrombotic effect of Celecoxib and risk of Myocardial Infarction

The present work was devoted to study the effects of celecoxib, a selective COX-2 inhibitor, on the risk of myocardial infarction [MI] induced experimentally in rats by subcutaneous injection of isoprenaline. The effects of celecoxib were compared with those of ibuprofen, the non-selective COX inhibitor. Sixty rats were used and divided into six groups, each of 10 rats. The groups received either saline [control group, group I], isoprenaline alone [group 11], isoprenaline and celecoxib [group III], isoprenaline and ibuprofen [group IV], celecoxib alone [group V], or ibuprofen alone [group VI], for two weeks. Acute Nil was induced in groups II, III, and iV of rats, by subcutaneous injection of isoprenaline [50 mg/kg/day] for two successive days. At the end of the study, all rats were subjected to ECG recording; measurement of serum levels of cardiac injury biomarkers total creatine kinase [CK] and subtype B [CK-MB]; assessment of ex-vivo platelet aggregation in response to ADP, collagen, and arachidonic acid; and histopathological examination of the isolated hearts. The results obtained revealed that induction of acute MI by isoprenaline resulted in significant ECG changes and marked rise in the levels of MI biomarkers, together with histological evidence of myocardial damage. These changes were associated with significant increase in platelet aggregation. Treatment with celecoxib leads to exaggeration of the MI manifestations induced by isoprenaline, with more marked changes in the ECG, serum MI markers, enhanced platelet aggregation, and significant increase in the area of cardiac infraction. On the contrary, treatment with ibuprofen produces no significant changes in the MI manifestations induced by isoprenaline, with similar percentage of infract surface area. It is concluded that selective COX-2 inhibitor, celecoxib can exaggerate myocardial damage and increase infarction size. The current data would suggest that the use selective COX-2 inhibitors, might lead to increased risk for thrombotic cardiovascular events probably via prothrombotic effect with enhanced platelet reactivity

Effect of carnosine on histamine release and mortality during compound 48/80-induced shock in rats

Carnosine is an endogenous dipeptide found at high concentrations in many tissues, Early studies have demonstrated a link between carnosine, free histidine and histamine synthesis following several types of physiologic stresses. However, the precise role of carnosine and histamine in the physiologic response to stress is unknown. The present work was conducted to study the effect of carnosine administration on the lethal shock induced in rats by compound 48/80, a histamine releasing agent and whether this effect was mediated by an action on mast cell histamine release, in-vitro. The in-vivo study included 6 groups of mature albino rats which received I.P. injection of either; saline, carnosine [200 mg/kg], compound 48/80 [5 mg/kg], or carnosine [50, 100 or 200 mg/kg] followed 30 mm later by compound 48/80 [5 mg/kg]. All rats were observed for 2 hours recording mortality and survival time in each group. The in-vitro study examined the effect on isolated rat mesenteric mast cells, of the following; saline, carnosine [2-16 mg/ml], compound 48/80 [1-8 ug/ml] and carnosine [2-16 mg/ml]+compound 48/80 [4 ug/ml]. Results showed that treatment with compound 48/50 [5 mg/kg] leads to 100% mortality in mature rats, while no deaths were observed in the saline and carnosine treated groups. Pretreatment with carnosine produced significant attenuation of the lethal effect of compound 48/80, with up to 67% protection in treated animals. Examination of mast cells revealed dose-dependent degranulation by compound 48/80 and insignificant changes by carnosine treatment. Addition of carnosine to compound 48/80 leads to significant inhibition of compound 48/80-induced mast cell degranulation and histamine release. It is concluded that carnosine could attenuate the lethal effect of compound 48/80-induced shock in rats and this protective effect was mediated, at least in pan, by decreasing histamine release from mast cells