Protective Effect Of Carvedilol Research Articles

Carvedilol attenuates inflammatory reactions of lipopolysaccharide-stimulated BV2 cells and modulates M1/M2 polarization of microglia via regulating NLRP3, Notch, and PPAR-γ signaling pathways.

Microglial cells coordinate immune responses in the central nervous system. Carvedilol (CVL) is a non-selective β-blocker with anti-inflammatory and anti-oxidant effects. This study aims to investigate the anti-inflammatory effects and the underlying mechanisms of CVL on lipopolysaccharide (LPS)-induced inflammation in microglial BV2 cells. BV2 cells were stimulated with LPS, and the protective effects of CVL were investigated via measurement of cell viability, reactive oxygen species (ROS), and interleukin (IL)-1β liberation. The protein levels of some inflammatory cascade, Notch, and peroxisome proliferator-activated receptor (PPAR)-γ pathways and relative markers of M1/M2 microglial phenotypes were assessed. Neuroblastoma SH-SY5Y cells were cultured with a BV2-conditioned medium (CM), and the capacity of CVL to protect cell viability was evaluated. CVL displayed a protective effect against LPS stress through reducing ROS and down-regulating of nuclear factor kappa B (NF-κB) p65, NLR family pyrin domain containing-3 (NLRP3), and IL-1β proteins. LPS treatment significantly increased the levels of the M1 microglial marker inducible nitric oxide synthase (iNOS) and M1-associated cleaved-NOTCH1 and hairy and enhancer of split-1 (HES1) proteins. Conversely, LPS treatment reduced the levels of the M2 marker arginase-1 (Arg-1) and PPAR-γ proteins. CVL pre-treatment reduced the protein levels of iNOS, cleaved-NOTCH1, and HES1, while increased Arg-1 and PPAR-γ. CM of CVL-primed BV2 cells significantly improved SH-SY5Y cell viability as compared with the LPS-induced cells. CVL suppressed ROS production and alleviated the expression of inflammatory markers in LPS-stimulated BV2 cells. Our results demonstrated that targeting Notch and PPAR-γ pathways as well as directing BV2 cell polarization toward the M2 phenotype may provide a therapeutic strategy to suppress neuroinflammation by CVL.

Comparing the Efficacy of Carvedilol and Celecoxib to Prednisolone in Acetic Acid-Induced Ulcerative Colitis in Male Albino Rats

Ulcerative colitis refers to destruction of mucosal layer of distal colon and rectum. Exact mechanism for pathophysiology is still unclear but inflammation and oxidative stress may play a caustic role. Neutrophil and monocyte infiltration results in free radical generation which damages intestinal mucosa. Many treatments as steroids are used to reduce inflammation but cannot cause remission. Carvedilol is a third-generation nonselective β-blocker which possesses anti-oxidant, anti-inflammatory properties and can reduce gastric ulceration. Celecoxib is a selective cyclooxygenase -2 (COX-2) inhibitor which decrease risk of gastrointestinal bleeding. The current study was designed to compare the efficacy of carvedilol and celecoxib to prednisolone in acetic acid-induced ulcerative colitis model. A total of 40 adult male albino rats were randomly divided into five groups: Control group: Rats received 2 ml of saline transrectal. Acetic acid (AA) group: Rats were transrectal injected with 2ml acetic acid. Prednisolone +AA group: Rats were pre-treated with prednisolone in a dose 4mg/kg /day. Carvedilol +AA group: Rats were pre-treated with carvedilol in a dose 30 mg/kg/day. Celecoxib +AA group: Rats were pre-treated with celecoxib in a dose 5mg/kg/day. All drugs were given orally for 7 days. At end of experiment, distal colon was removed, one part of specimen was preserved in 10% formalin for histological examination and other part was homogenized for evaluation of tumor necrosis factor alpha (TNF-α), reduced glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO) and mitogen-activated protein kinase ( p38 MAPK). Data of present study revealed that treatment of rats with carvedilol or celecoxib before induction of colitis significantly reduced levels of TNF-α, MDA, NO and mRNA level of p38 MAPK while both drugs increased GSH level. Protective effects of Carvedilol and celecoxib are due to anti-inflammatory, anti-oxidant effects and ability to decrease synthesis of MAPK which reduce cytokines signaling in epithelial cells of gut mucosa.

Evaluation of the Effect of Carvedilol in Preventing Right Ventricular Dysfunction in Breast Cancer Patients Receiving Anthracycline.

Today, it has been shown that it is possible for right ventricular (RV) wall motion abnormalities or RV functional disorders to occur during cancer treatment. Now, considering the effect of carvedilol on beta 1, 2, and alpha receptors and its antioxidant properties, it seems that it can prevent RV abnormalities. Therefore, the aim of this study was to investigate the possible protective effects of carvedilol in preventing RV dysfunction in patients with breast cancer treated with anthracyclines. The present single-blind clinical trial study was performed on 23 patients with breast cancer that 12 of them received only the anthracycline antineoplastic doxorubicin (Adriamycin®) chemotherapy (control group) and 11 patients received carvedilol in addition to anthracycline. To evaluate the effect of carvedilol, patients underwent transthoracic echocardiography before intervention and 2 weeks after the end of treatment with anthracyclines. The two parameters of RV ejection fraction and RV fractional area change in the carvedilol group with a mean of 66.41% ± 8.10% and 51.85% ± 6.89% were slightly higher than the control group with a mean of 64.58% ± 6.83% and 50.48 ± 5.79%, respectively, which was not statistically significant (P > 0.05). In contrast, RV S wave tissue Doppler imaging (S-TDI) in the control group with a mean of 0.13 ± 0.02 m/s was significantly lower than the carvedilol group with a mean of 0.14 ± 0.02 m/s (P = 0.022). According to the results of the present study, the effect of using carvedilol as a preservative on improving RV function was seen compared to the control group, although this difference was not statistically significant.

Carvedilol alleviates lipopolysaccharide (LPS)-induced acute lung injury by inhibiting Ras homolog family member A (RhoA)/ROCK activities

ABSTRACT Carvedilol possess multiple functions such as antioxidation and neuroprotection RhoA/ROCK is reported to participate in acute lung injury (ALI). The aim of the present study was to explore the role of carvedilol in LPS-induced ALI. BEAS2B cells were subjected to LPS for the construction of in vitro ALI model. After that, the protective effects of carvedilol were evaluated by Cell Counting Kit-8 (CCK-8). The activities of RhoA/ROCK were then measured to confirm its association with carvedilol by quantitative reverse transcription PCR (RT-qPCR) and Western blot. Then, the cell viability, inflammatory responses, oxidative stress and apoptosis were detected by CCK-8, enzyme linked immunosorbent assay (ELISA), oxidative stress detection kits, and TdT-mediated dUTP Nick-End Labeling (TUNEL) respectively. Inflammation- and apoptosis-related markers were also measured by Western blot. The cell viability reduced by LPS in BEAS2B cells was elevated by carvedilol. Moreover, RhoA/ROCK were found to be suppressed by carvedilol administration. The cell viability, inflammation, oxidative stress and apoptosis of LPS-induced BEAS2B cells were aggravated upon RhoA was overexpressed. Collectively, carvedilol exerts a protective effect against LPS-induced injury that could be ascribed to its anti-inflammatory and antioxidative character through modulating the RhoA/ROCK activities.

Carvedilol attenuates acrylamide-induced brain damage through inhibition of oxidative, inflammatory, and apoptotic mediators.

Acrylamide is a potent neurotoxic compound and has harmful effects on brain cells. Acrylamide promotes oxidative, inflammatory, and apoptotic mediators in the CNS leading to neurological disorders. The goal of the current study was to examine the potential protective effect of carvedilol and its underlying mechanisms in a mouse model of acrylamide-induced brain injury. Mice were treated with acrylamide (50 mg/kg/day, IP) and carvedilol (5 and 10 mg/kg/day, oral) for 11 continuous days. At the end of the experiment, mice were subjected to gait assessment. They were sacrificed and brain tissues were collected for histological and biochemical analysis. The results showed that treatment of mice with carvedilol decreased acrylamide-induced bodyweight loss, abnormal gait, and histopathological damage in the brain tissue. Carvedilol treatment significantly reduced the levels of malondialdehyde (MDA) and carbonyl protein and increased the levels of glutathione (GSH), catalase, superoxide dismutase (SOD), nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). Carvedilol treatment also decreased myeloperoxidase (MPO) activity, expression of nuclear factor kappa B (NF-κB), inducible nitric oxide synthase (iNOS), overproduction of nitric oxide (NO) and proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 in the brain of mice exposed to acrylamide. Furthermore, administration of carvedilol significantly decreased the levels of bax, cytochrome-c, and caspase-3 as markers of apoptosis in acrylamide-treated mice. These findings indicate that carvedilol is able to attenuate acrylamide-induced damage to the CNS by inhibition of oxidative stress, inflammation, and apoptosis.

Liposomal Resveratrol and/or Carvedilol Attenuate Doxorubicin-Induced Cardiotoxicity by Modulating Inflammation, Oxidative Stress and S100A1 in Rats.

Doxorubicin (DOX) is a cytotoxic anthracycline antibiotic and one of the important chemotherapeutic agents for different types of cancers. DOX treatment is associated with adverse effects, particularly cardiac dysfunction. This study examined the cardioprotective effects of carvedilol (CAR) and/or resveratrol (RES) and liposomal RES (LIPO-RES) against DOX-induced cardiomyopathy, pointing to their modulatory effect on oxidative stress, inflammation, S100A1 and sarco/endoplasmic reticulum calcium ATPase2a (SERCA2a). Rats received CAR (30 mg/kg) and/or RES (20 mg/kg) or LIPO-RES (20 mg/kg) for 6 weeks and were challenged with DOX (2 mg/kg) twice per week from week 2 to week 6. DOX-administered rats exhibited a significant increase in serum creatine kinase-MB (CK-MB), troponin-I and lactate dehydrogenase (LDH) along with histological alterations, reflecting cardiac cell injury. Cardiac toll-like receptor 4 (TLR-4), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α and interleukin (IL)-6 protein expression were up-regulated, and lipid peroxidation was increased in DOX-administered rats. Treatment with CAR, RES or LIPO-RES as well as their alternative combinations ameliorated all observed biochemical and histological alterations with the most potent effect exerted by CAR/LIPO-RES. All treatments increased cardiac antioxidants, and the expression of S100A1 and SERCA2a. In conclusion, the present study conferred new evidence on the protective effects of CAR and its combination with either RES or LIPO-RES on DOX-induced inflammation, oxidative stress and calcium dysregulation.

Carvedilol Diminishes Cardiac Remodeling Induced by High-Fructose/High-Fat Diet in Mice via Enhancing Cardiac β-Arrestin2 Signaling.

Insulin resistance (IR) is a well-known risk factor for cardiovascular complications. This study aimed to investigate the effect of a dietary model of IR in mice on cardiac remodeling, cardiac β-arrestin2 signaling, and the protective effects of carvedilol as a β-arrestin-biased agonist. Insulin resistance was induced by feeding mice high-fructose/high-fat diet (HFrHFD) for 16 weeks. Carvedilol was adiministered for 4 weeks starting at week 13. At the end of the experiment, body weight, heart weight, left and right ventricular thickness, visceral fat weight, fasting blood glucose (FBG), serum insulin, IR index, and serum endothelin-1 were measured. In addition, cardiac tissue samples were histopathologically examined. Also, cardiac levels of cardiotrophin-1, β-arrestin2, phosphatidylinositol 4,5 bisphosphate (PIP2), diacylglycerol (DAG), and phosphoserine 473 Akt (pS473 Akt) were measured. Results showed significant increases in the FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, cardiac fibrosis, and degenerated cardiac myofibrils in HFrHFD-fed mice associated with a significant reduction in cardiac levels of cardiotrophin-1, β-arrestin2, PIP2, and pS473 Akt. On the other hand, carvedilol significantly reduced the heart weight, FBG, serum insulin, IR index, serum endothelin-1, cardiac DAG, left ventricular thickness, right ventricular fibrosis, and degeneration of cardiac myofibrils. In addition, carvedilol significantly increased cardiac levels of cardiotrophin-1, β-arrestin2, PIP2, and pS473 Akt. Carvedilol enhances cardiac β-arrestin2 signaling and reduces cardiac remodeling in HFrHFD-fed mice.

The cardioprotective effects of carvedilol on ischemia and reperfusion injury by AMPK signaling pathway

Carvedilol, a third generation beta blocker, is in clinical use for heart failure patients. However, besides adrenergic receptor blockade, the pharmacological effects of carvedilol on cardiomyocytes remain unknown. AMP-activated protein kinase (AMPK) is an emerging target recognized for heart failure treatment. The mechanical properties and intracellular Ca2+ properties were measured in isolated cardiomyocyte contractile functions in response to ischemic stress. Treatment of cardiomyocytes with carvedilol augmented phosphorylation of AMPK and downstream acetyl CoA carboxylase (ACC), and ameliorated hypoxia-induced impairment in maximal velocity of shortening (+dL/dt) and relengthening (-dL/dt), and the impaired peak height and peak shortening (PS) amplitude caused by hypoxia. Carvedilol treatment improved calcium homeostasis with rescuing the peak Ca2+ signal, the maximum rate of Ca2+ change during contraction (+dF/dt) and the maximum rate of Ca2+ change during relaxation (-dF/dt) under hypoxia conditions. In mouse hearts perfused ex vivo with carvedilol, the function of post-ischemia left ventricle was improved and an augmentation in myocardial glucose uptake and glucose oxidation, and inhibition of fatty acid oxidation during ischemia and reperfusion. The protective effect of carvedilol was further supported in an in vivo regional ischemia model by ligation of left anterior descending coronary artery (LAD), mice treated with carvedilol followed by LAD occlusion and reperfusion showed significant size reduction in infarcted myocardium and improved cardiac functions. Therefore, Carvedilol as a clinical drug can modulate cardiac AMPK signaling pathway to reduce ischemic insults by ischemia and reperfusion.

Carvedilol Inhibits Matrix Metalloproteinase-2 Activation in Experimental Autoimmune Myocarditis: Possibilities of Cardioprotective Application.

Acute myocarditis is a potentially lethal inflammatory heart disease that frequently precedes the development of dilated cardiomyopathy and subsequent heart failure. At present, there is no effective standardized therapy for acute myocarditis, besides the optimal care of heart failure and arrhythmias in accordance with evidence-based guidelines and specific etiology-driven therapy for infectious myocarditis. Carvedilol has been shown to be cardioprotective by reducing cardiac pro-inflammatory cytokines present in oxidative stress in certain heart diseases. However, effects of carvedilol administration in acute myocarditis with its impact on matrix metalloproteinases' (MMPs) activation have not been elucidated. Carvedilol in 3 doses (2, 10, and 30 mg/kg) was given daily to 3 study groups of rats (n = 8) with experimental autoimmune myocarditis by gastric gavage for 3 weeks. In comparison to untreated rats (n = 8) with induced myocarditis, carvedilol significantly prevented the left ventricle enlargement and/or systolic dysfunction depending on the dose in study groups. Performed zymography showed enhanced MMP-2 activity in untreated rats, while carvedilol administration reduced alterations. This was accompanied by prevention of troponin I release and myofilaments degradation in cardiac muscle tissue. Additionally, severe inflammatory cell infiltration was detected in the nontreated group. Carvedilol in all doses tested, had no impact on severity of inflammation. The severity of inflammation did not differ between study groups and in relation to the untreated group. The protective effects of carvedilol on heart function observed in the acute phase of experimental autoimmune myocarditis seem to be associated with its ability to decrease MMP-2 activity and subsequently prevent degradation of myofilaments and release of troponin I while not related to suppression of inflammation.

The β‐blocker carvedilol blocks UVB‐induced DNA damage and apoptosis of skin

β‐blockers are common pharmacological antagonists of the catecholamine activated β‐adrenergic receptors (β‐ARs). Traditionally prescribed for cardiovascular diseases such as hypertension, this class of drugs has recently been proposed with new uses in cancer treatment and prevention. Our previous studies showed that carvedilol, a nonselective GRK/β‐arrestin biased agonist, prevents skin carcinogenesis in vitro and in vivo. In the present study, we aimed at investigating the effects and mechanism of carvedilol on ultraviolet B (UVB) induced skin DNA damage and apoptosis. To assess the effects of carvedilol in vitro, the tumor promotion sensitive mouse epidermal JB6 P+ cells were treated with H2O2 or UVB to induce cell death and apoptosis. Protective effects of carvedilol was observed through cell counting, SRB cytotoxicity assay and apoptosis assay. Carvedilol effectively prevented H2O2 induced formation of reactive oxygen species in JB6 P+ cells. To explore the mechanism of action, JB6 P+ cells were treated with UVB followed by treatment with carvedilol (to avoid sunscreen effect) in various concentrations and time points. As expected, Western Blot analysis showed that the protein levels of p53 and phospho‐p53 at ser15 were induced by UVB treatment, whereas the effect of UVB on p53 was attenuated by carvedilol. We further examined the effects of topically administered carvedilol on SKH‐1 hairless mice irradiated with a single minimal effective dose (MED) of UVB (200 mJ/cm2). Our results showed that carvedilol protected UVB induced cyclobutene pyrimidine dimer (CPD) formation and apoptosis, 6 and 24 hours after UVB exposure. Consistently, the increased levels of total p53 and phospho‐p53 at Ser15 in mouse skin induced by UVB was decreased after carvedilol treatment. The change in p53 did not occur at the mRNA level, given RT‐PCR analysis failed to detect any change in the Tp53 gene. From these results, we conclude that carvedilol exhibits a protective effect against UVB induced DNA damage and apoptosis, partly related to its effect on UVB‐induced p53. These results further support the notion that the β‐blocker carvedilol may be re‐purposed for skin cancer prevention.

Protective Effect of Carvedilol on Paracetamol-induced Hepatotoxicity; Role of Modulation Inflammation and Lipid Peroxidation

Protective Effect of Carvedilol on Paracetamol-induced Hepatotoxicity; Role of Modulation Inflammation and Lipid Peroxidation

Dual targeting of TNF-α and free radical toxic stress as a promising strategy to manage experimental polycystic ovary

Context: It is now clear that oxidative stress (OS) and chronic low-grade inflammation are two main pathways involved in polycystic ovary syndrome (PCOS) pathogenesis. Therefore, simultaneous targeting of these pathways by means of carvedilol and Semelil (ANGIPARS™), as established medicines with dual anti-cytokine and anti-oxidant potential may be a therapeutic alternative approach to the current treatments.Objective: The objective of this study is to study the protective effects of carvedilol and ANGIPARS™ on inflammatory and oxidative response in hyperandrogenism-induced polycystic ovary (PCO).Materials and methods: The murine model of PCO was induced by letrozole (1 mg/kg/d; orally) and effective doses of carvedilol (10 mg/kg/d; orally) and ANGIPARS™ (2.1 mg/kg/d; orally) were administrated for 21 d in PCO and non-PCO healthy rats. Ovarian folliculogenesis, sex hormones concentrations, OS, inflammatory, and metabolic biomarkers were assessed in serum and ovaries.Results: PCO rats exhibited ovarian cystogenesis which was preserved by the application of carvedilol and ANGIPARS™. In comparison with controls, decreased level of the total antioxidant power (TAP) and higher levels of reactive oxygen species (ROS) and lipid peroxidation (LPO) in serum and ovaries (2.41 ± 0.67 versus 0.72 ± 0.11; and 0.17 ± 0.04 versus 0.05 ± 0.01; 5.48 ± 1.30 versus 10.56 ± 0.77; and 7.06 ± 1.94 versus 17.98 ± 0.98; p < 0.05, respectively) were detected in PCO rats. Moreover, the PCO rats exhibited hyperandrogenism due to a 3.7-fold increase in serum testosterone concentration (35.04 ± 3.17 versus 131.09 ± 13.24; p < 0.05) along with a 2.98-fold decrease in serum progesterone (6.19 ± 0.40 versus 18.50 ± 1.03; p < 0.05) and 5.2-fold decrease in serum estradiol (9.30 ± 0.61 versus 48.3 ± 2.10; p < 0.05) when compared with those of the control group. However, similar to the control group, normal levels of OS markers and sex hormones were detected in ANGIPARS™ and carvedilol co-treated PCO rats. Besides, when compared with controls, increased levels of TNF-α (770.75 ± 42.06 versus 477.14 ± 28.77; p < 0.05) and insulin (1.27 ± 0.10 versus 0.36 ± 0.05; p < 0.05) in PCO rats were significantly inhibited by carvedilol and ANGIPARS™ co-treatment.Discussion and conclusion: We evidenced the beneficial effects of carvedilol and ANGIPARS™ in PCO, which underpin the new alternative approach in using these kinds of medicines in female reproductive disorders.

Carvedilol promotes neurological function, reduces bone loss and attenuates cell damage after acute spinal cord injury in rats.

Acute spinal cord injury (SCI) leads to permanent functional deficits via mechanical injury and secondary mechanisms, but the therapeutic strategy for SCI is limited. Carvedilol has been shown to possess multiple biological and pharmacological properties. The of the present study was to investigate the possible protective effect of carvedilol in SCI rats. An acute SCI rat model was established and neurological function was tested. After carvedilol (10 mg/kg, oral gavage) treatment for 21 days, the status of osteoporosis, neuron damage, astrocyte activation, inflammation, oxidative stress and apoptosis were evaluated in rats. Carvedilol significantly improved locomotor activity that was decreased by SCI. In addition, carvedilol promoted bone growth by regulating the expression of nuclear factor-κB ligand (receptor activator of nuclear factor-κB ligand; RANKL) and osteoprotegerin (OPG), inactivating osteoclasts and thereby increasing bone mineral density in tibias. In addition, carvedilol reduced SCI-induced neural damage, increased neuron number and reduced astrocyte activation in the spinal cord. Furthermore, the production and mRNA expression of tumour necrosis factor-α, interleukin (IL)-1β and IL-6 were significantly reduced, reduced glutathione content and superoxide dismutase activity were markedly increased and malondialdehyde content was markedly decreased in the spinal cords of carvedilol-treated rats. These results indicate that carvedilol exhibits anti-inflammatory and anti-oxidative effects in SCI rats. In addition, the expression of Fas and Fas ligand was reduced by carvedilol treatment, which, in turn, reduced cleaved caspase 3 expression and finally decreased the number of apoptotic cells in the spinal cord. In conclusion, carvedilol promotes neurological function, reduces bone loss and attenuates cell damage after acute SCI in rats.

Carvedilol ameliorates early diabetic nephropathy in streptozotocin-induced diabetic rats.

Diabetic nephropathy results in end-stage renal disease. On the other hand, carvedilol has been reported to have various pharmacological properties. The aim of this study therefore is to evaluate the possible protective effect of carvedilol on streptozotocin-induced early diabetic nephropathy and various mechanisms underlie this effect in rats. Single i.p. injection of streptozotocin (65 mg/kg) was administered to induce early diabetic nephropathy in Wistar rats. Oral administration of carvedilol at a dose level of 1 and 10 mg/kg daily for 4 weeks resulted in nephroprotective effect as evident by significant decrease in serum creatinine level, urinary albumin/creatinine ratio, and kidney index as well as renal levels of malondialdehyde, nitric oxide, tumor necrosis factor-α, and cyclooxygenase-2 with a concurrent increase in creatinine clearance and renal reduced glutathione level compared to diabetic untreated rats. The protective effect of carvedilol was confirmed by renal histopathological examination. The electron microscopic examination indicated that carvedilol could effectively ameliorate glomerular basement membrane thickening and podocyte injury. In conclusion, carvedilol protects rats against streptozotocin-induced early diabetic nephropathy possibly, in part, through its antioxidant as well as anti-inflammatory activities, and ameliorating podocyte injury.

Carvedilol efficiently protects kidneys without affecting the antitumor efficacy of cisplatin in mice

Cisplatin is an effective anticancer drug which has been used to treat a wide range of tumors for the last 30years. However, its use is associated with nephrotoxicity. Protective strategies have been reported, but their impact on the antitumor activity of cisplatin has not been clarified. We have previously reported the protective potential of carvedilol against cisplatin nephrotoxicity in tumor-free rats. Therefore, in the present study we used a tumor-bearing model to investigate the impact of carvedilol on the antitumor activity of cisplatin. The renal damage induced by cisplatin and the protective effect of carvedilol were demonstrated by the levels of blood urea nitrogen and plasma creatinine as well as by renal histopathology and immunohistochemistry. The mechanism of protection was associated with significantly decreased (i) oxidative stress markers, (ii) Bax expression, (iii) caspase-3 activity and (iv) TUNEL labeling for apoptosis. More importantly, evaluation of tumor mass, tumor remission rate and the survival curve showed that carvedilol did not impair the antitumor action of cisplatin. These findings suggest that the mechanisms underlying the nephrotoxic and the antitumor activity of cisplatin might be different. This is the first study to report such findings. Compared to other reported potential cytoprotectors against cisplatin-induced nephrotoxicity, carvedilol stands out due to the fact that it is already clinically-employed and well tolerated by the patients. Based on these features and on the present findings, carvedilol is a very promising candidate for future clinical trials as nephroprotector in patients treated with cisplatin.

The effect of carvedilol on serum and tissue oxidative stress parameters in partial ureteral obstruction induced rat model

Although the pathological mechanism underlying kidney damage is not completely understood, it has been reported that reactive oxygen species (ROS) formed during ureteral obstruction may play an important role in this process. Carvedilol has been used in a limited number of studies examining oxidative injury. The aim of this study was to investigate the effect of carvedilol on serum and tissue oxidative stress parameters in the partial unilateral ureteral obstruction (PUUO)-induced rat model. To our knowledge, the protective effects of carvedilol in the PUUO-induced rat model have not been reported. Twenty-six male Wistar albino rats, age 5.5 to 6 months and weighing 250 to 300 g, were used in this study. The rats were randomly divided into three groups. In Group 1 (n = 9), the control group, a sham operation was performed. In Group 2 (n = 8), the PUUO group, the left ureter was embedded into the psoas muscle to create PUUO and maintained for 7 days. In Group 3 (n = 9), carvedilol was orally administered to the rats (2 mg/kg). After the establishment of PUUO, carvedilol was given for the following 7 days. After partial unilateral ureteral obstruction, a nephrectomy was performed to determine the blood and tissue levels of superoxide dismutase (SOD), malondialdehyde (MDA), protein carbonyl (PC), and nitric oxide (NO). The median SOD, MDA, PC, and NO levels in the tissues were 0.006 U/mg protein, 5.11 nmol/g protein, 4.31 nmol/mg protein, and 0.337 μmol/g protein in the control group, respectively. There was a significant increase in tissue SOD (p = 0.014), MDA (p = 0.002), and NO (p = 0.004) levels in Group 2. However, a statistically significant difference was not observed in PC (p = 0.847) enzymatic activity in Group 2. When compared with Group 2, carvedilol treatment caused a reduction in NO (p = 0.003), and PC (p = 0.001) activities in Group 3. The serum SOD (p = 0.004), MDA (p = 0.043), PC (p = 0.043), and NO (p = 0.001) levels were significantly different in Group 3 compared with Group 2. Administration of carvedilol also reduced the detrimental histopathologic effects caused by PUUO. According to histopathological examination of the renal tissues, the inflammation rates were 22.2%, 87.5% and 33.3% in Groups 1, 2, and 3, respectively (p < 0.05). The results of the present study show that partial unilateral ureteral obstruction caused oxidative stress in the serum and kidney tissues of rats, and treatment with carvedilol reduced the harmful effects of ureteral obstruction.

Protective Effect of Carvedilol on Adriamycin-Induced Left Ventricular Dysfunction in Children With Acute Lymphoblastic Leukemia

BackgroundAdriamycin (ADR) is a potent chemotherapeutic agent widely used in the treatment of childhood acute lymphoblastic leukemia (ALL); its clinical use is limited owing to its marked cardiotoxicity. The present study investigated the possible protective role of carvedilol on ADR-induced left ventricular dysfunction in children with ALL. Methods and ResultsFifty children with newly diagnosed ALL were included in this study. They were divided into 2 equal groups: 1) ADR; and 2) ADR + carvedilol. Patients were evaluated with conventional 2-dimensional echocardiographic examination (2D), pulsed tissue Doppler (PTD), and 2-dimensional longitudinal strain echocardiography (2DS) before and after therapy. Plasma lactic dehydrogenase (LDH), creatine phosphokinase (CPK), and troponin I levels were also determined before and after therapy. ADR treatment reduced left ventricular systolic dysfunction as assessed by a significant decrease in fractional shortening (FS) (2D) and global peak-systolic strain (GPSS; 2DS). In addition, ADR treatment significantly increased plasma troponin I and LDH. Pretreatment of ADR-treated patients with carvedilol resulted in a significant increase in FS (2D) and GPSS (2DS). Furthermore, carvedilol pretreatment inhibited ADR-induced increase in plasma troponin I and LDH. ConclusionsThese results suggested a protective role of carvedilol against ADR-induced cardiotoxicity.

Carvedilol Protects Against Apoptotic Cell Death Induced by Cisplatin in Renal Tubular Epithelial Cells

Cisplatin is a highly effective chemotherapeutic drug; however, its use is limited by nephrotoxicity. Studies showed that the renal injury produced by cisplatin involves oxidative stress and cell death mediated by apoptosis and necrosis in proximal tubular cells. The use of antioxidants to decrease cisplatin-induced renal cell death was suggested as a potential therapeutic measure. In this study the possible protective effects of carvedilol, a beta blocker with antioxidant activity, was examined against cisplatin-induced apoptosis in HK-2 human kidney proximal tubular cells. The mitochondrial events involved in this protection were also investigated. Four groups were used: controls (C), cisplatin alone at 25 μM (CIS), cisplatin 25 μM plus carvedilol 50 μM (CV + CIS), and carvedilol alone 50 μM (CV). Cell viability, apoptosis, caspase-9, and caspase-3 were determined. Data demonstrated that carvedilol effectively increased cell viability and minimized caspase activation and apoptosis in HK-2 cells, indicating this may be a promising drug to reduce nephrotoxicity induced by cisplatin.

Protective effect of carvedilol on daunorubicin-induced cardiotoxicity and nephrotoxicity in rats

Daunorubicin (DNR) is one of the anthracycline anti-tumor agents widely used in the treatment of acute myeloid leukemia. However, the clinical use of DNR has been limited by its undesirable systemic toxicity, especially in the heart and kidney. This study was designed to test the effectiveness of carvedilol, a nonselective β-blocker against DNR-induced cardiotoxicity and nephrotoxicity. Rats were treated with a cumulative dose of 9 mg/kg body weight DNR (i.v.). Carvedilol was administered orally every day for 6 weeks. DNR rats showed cardiac and nephrotoxicities as evidenced by worsening cardiac and kidney functions, which were evaluated by hemodynamic and echocardiographic studies, and by measuring protein in urine, levels of urea and creatinine in serum, lipid profiles, malondialdeyde level and the total level of glutathione peroxidase activity in both heart and kidney tissues. These changes were reversed by treatment with carvedilol, which resulted in significant improvement in the cardio-renal function. Furthermore, carvedilol down-regulated matrix metalloproteinase-2 expression in the heart, increased nephrin expression in the kidney, and attenuated the increased protein expression of NADPH oxidase subunits in heart and kidney. Moreover, carvedilol reduced myocardial and renal apoptosis and improved the histopathological changes in heart and kidney induced by DNR. In conclusion, the present study demonstrated a beneficial effect of carvedilol treatment in the prevention of DNR-induced cardiotoxicity and nephrotoxicity by reversing the oxidative stress and apoptosis.

Protective Effects of Carvedilol Against Anthracycline-Induced Cardiomyopathy

Protective Effects of Carvedilol Against Anthracycline-Induced Cardiomyopathy