Protective effects of necrostatin-1 on doxorubicin-induced cardiotoxicity in rat heart.

Background: Doxorubicin (Dox) is one of the most effective antineoplastic drugs which has severe cardiotoxic effects, limiting its clinical usage. Though the exact mechanism of doxorubicin-induced cardiotoxicity is yet to be elucidated, it is shown that production of reactive oxygen species (ROS) increases oxidative stress and leads to cardiomyocyte apoptosis and necroptosis which is also defined as a programmed cell death.Purpose: In the present study, we investigate the effects of necrostatin-1 (Nec-1)-an inhibitor of receptor interaction proteins 1 (RIP1) and necroptosis-on doxorubicin-induced cardiotoxicity in rats.Research Design: Hearts were isolated and perfused by the Langendorff system in all four groups. Perfusion pressure (PP), left ventricular developed pressure (LVDP) and heart rate per minute (HR), LV (dP/dt) max, and LV (dP/dt) min which shows cardiac contractility and relaxation were recorded.Results: Results showed that PP significantly increased with Dox treatment and significantly decreased with Nec-1 treatment, while HR, LVDP, LV (dP/dt) max, and LV (dP/dt) min values significantly decreased with the Dox-treated group and significantly increased with Nec-1 treatment. Also with Nec-1 treatment, gene expression levels of anti-apoptotic Bcl-2 significantly increased and pro-apoptotic protein Bax, apoptotic marker caspase-3, and Nox-2 significantly decreased compared to the Dox-treated group. In heart tissues, MDA levels were significantly increased with Dox and decreased with Nec-1 treatment. These results were supported by the histological analysis indicated that Nec-1 reduced doxorubicin-induced cellular injury.Conclusions: In conclusion, our data indicate that Nec-1 ameliorates doxorubicin-induced cardiotoxicity by reducing oxidative stress injury and attenuating apoptosis and necroptosis.

Impact of N-acetylcysteine and etodolac treatment on systolic and diastolic function in a rat model of myocardial steatosis induced by high-fat-diet.

OBJECTIVES: Obesity is a worldwide problem, leading to cardiomyopathy. Oxidative stress and inflammation have been reported to play significant roles in developing obesity cardiomyopathy. N-acetylcysteine is a glutathione prodrug that preserves liver against steatosis via constraining the production of reactive oxygen species. Etodolac is a nonsteroidal anti-inflammatory drug which has been demonstrated to protect liver against fibrosis. The aim of the present study was to evaluate and compare the effects of N-acetylcysteine and etodolac on impaired cardiac functions due to high-fat-diet (HFD) induced myocardial steatosis in rats. MATERIAL AND METHODS: Thirty-two male Sprague-Dawley rats were randomly divided into four groups. Control group was maintained on standard-rat-basic-diet (SD) for 20 weeks, while HFD was given to three study groups for 20 weeks. Then N-acetylcysteine was given to one of the study groups (HFD+NAC), and etodolac to another group (HFD+ETD) as a supplement for 4 weeks while all groups were continued on SD. At the end of the study periods, hearts were examined by Langendorff technique and rat livers were evaluated histologically. RESULTS: HFD and HFD+ETD groups presented with significantly higher steatosis and fibrosis in liver compared to other groups. HFD+NAC preserved diastolic functions. Also HFD+NAC and HFD+ETD groups had significantly better systolic funtions than HFD group. CONCLUSIONS: Obesity is associated with diastolic dysfunction rather than systolic dysfunction. NAC may protect the heart against diastolic dysfunction due to obesity. NAC and etodolac treatment improve systolic function, even in the absence of systolic dysfunction.

Protective effects of ethyl pyruvate in cisplatin-induced nephrotoxicity.

This study was performed to investigate the effect of ethyl pyruvate on changes in renal functions and oxidative stress related renal injury caused by cisplatin (cis-dichlorodiammine platinum-II; CDDP). Male Wistar albino rats were divided into four groups (n = 8): (1) control group (1 ml Ringer's lactate solution i.p.); (2) ethyl pyruvate (EP) group (50 mg/kg Ringer's EP solution (REPS) i.p.); (3) cisplatin group (a single dose of cisplatin (5 mg/kg, i.p.); and (4) cisplatin + EP group (a single dose of cisplatin (5 mg/kg, i.p.) + REPS 50 mg/kg/day, i.p.) for five days. At the sixth day, kidneys of rats were mounted to a Langendorff apparatus. Renal perfusion pressures were recorded. Blood samples were taken for serum urea, creatinine, total oxidant status (TOS), total antioxidant status (TAS) and oxidative stres index (OSI) evaluations. Kidney tissues were obtained for malondialdehyde (MDA) analyses and histopathological examination. Perfusion pressures, serum urea, creatinine, TOS, OSI and tissue MDA levels were found significantly higher, whereas TAS was notably lower in cisplatin group. Histopathological examination showed apparent renal paranchymal injury in cisplatin group. In cisplatin + REPS group, perfusion pressures, serum urea, creatinine and tissue MDA levels were decreased. Moreover, EP co-administration provided less inflammatory cell infiltration, tubular dilatation, whereas TOS, TAS and OSI improved significantly versus cisplatin group. These findings show that EP has protective effects against cisplatin nephrotoxicity.