Doxorubicin-induced Cardiac Toxicity In Rats Research Articles

Cardioprotective effect of chelidonic acid against doxorubicin-induced cardiac toxicity in rats

Introduction and objectivesThe current study evaluates the effect of chelidonic acid on doxorubicin-induced cardiac toxicity. Chelidonic acid (CA) is a natural pyran-skeleton heterocyclic compound found in rhizomes of the perennial plant, celandine (Chelidonium majus). MethodsWistar rats were given an intraperitoneal injection of doxorubicin (1.25 mg/kg, cumulative dose of 20 mg/kg) four times per week for a duration of four weeks to induce cardiotoxicity. CA treatment (10, 20, and 40 mg/kg orally for four weeks) was started together with doxorubicin. ResultsCA treatment reduced myocardial damage and improved cardiac dysfunction in doxorubicin-treated rats. It improved blood pressure, restored ST wave height and normalized the QTc interval compared to the rats treated only with doxorubicin. Administration of CA for four weeks reduced left ventricular end-diastolic pressure. Moreover, CA treatment decreased the level of cardiac markers such as creatine kinase-myocardial band (CK-MB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and cardiac troponin-T. Masson's trichrome, hematoxylin, and eosin staining of heart tissue revealed that CA attenuated the deleterious effects of doxorubicin and prevented further damage and fibrosis in rats. ConclusionThe study findings confirm that CA treatment can protect the myocardium against doxorubicin-induced cardiotoxicity.

Synergistic impacts of Montelukast and Klotho against doxorubicin-induced cardiac toxicity in Rats.

Doxorubicin (DOX) is a powerful antitumor agent with a well-known cardiaotoxic side effects. In the current study, the ameliorative combined impacts of montelukast (Mont) and Klotho against doxorubicin-induced cardiac toxicity were examined. Fifty-six adult male rats (2months age and weighting 150-200 g) were grouped into 7 groups (8 rats per group). Animals received doxorubicin alone or in combination with either Mont or Klotho. After 2weeks of treatments, serum samples were examined to assess the changes in cardiac activity biomarkers such as LDH, CK-MB, cardiac troponin-I (cTn-I), and heart fatty acid binding protein (H-FABP). Serum changes of IL-6, inducible nitric oxide synthase (iNOS), and caspase-3 levels were assayed. The oxidative stress biomarkers such as total antioxidant capacity (TAC) and inflammatory (rat IL-1β and rat TNF-α,) and anti-inflammatory (rat IL-10) cytokines were examined. Heart histology and transforming growth factor-β1 (TGF-β1) immunoreactivity were measured. DOX induced cardiomyopathy, which was reflected by the increases in all examined cardiac parameters. Real-time PCR confirmed that DOX upregulated the expression of TNF-α and IL-1β and decreased the expression of IL-10. Moreover, DOX showed marked elevation in the ST segment T wave complex, causing profound tachycardia. Heart histology assessments showed cardiac cell necrosis, inflammatory cell infiltration, interstitial congestion, and increased TGF-β1 immunoreactivity. Montelukast and Klotho administration ameliorated all the altered parameters when administered alone or in combination to DOX-intoxicated rats. Klotho was more effective compared with montelukast in terms of reductions in heart rate, ST segment T wave complex elevation, cardiac enzymes (lactate dehydrogenase; LDH, creatine kinase-MB; CK-MB, cardiac troponin I; cTn-I, heart fatty acid binding protein; H-FABP) cardiac histology, and caspase-3 levels and increases in TAC activity. Montelukast was more effective in reducing serum levels of IL6 and iNOS, expression of TNF-α and IL-1β, and the upregulation of IL-10 expression. The co-administration of both drugs led to significantly more synergistic results in terms of reducing cardiac toxicity. In conclusion, montelukast and Klotho either alone or in combination were confirmed to be effective in suppressing DOX-induced cardiac toxicity in rats.

The Potential protective role of astaxanthin on doxorubicin-induced cardiac toxicity in rats

Abstract Background and Aim of Work Doxorubicin (DOX) is one of the most commonly used effective anticancer drugs, through its inhibition of topoisomerase II, DNA replication and repair. In addition, DOX leads to generation of semiquinone free radicals and oxygen free radicals which attack DNA and oxidize DNA bases. However, the clinical use of doxorubicin is limited by its adverse effects such as cardiotoxicity, which is acute and occurs within 2-3 days of its administration. Recently, the potential health benefits of Astaxanthin were investigated, however, the protective effect of astaxanthin supplementation on cardiac dysfunction induced by Doxorubicin is not clearly investigated. The aim of the present study is directed to investigate the possible role of astaxanthin (xanthophyll carotenoid) in protection against DOX- induced cardiac toxicity, and to elucidate the underlying mechanism(s). Materials and Methods Animals used were 47 adult male albino rats, which were randomly allocated into four groups. Control group(C): received 0.1ml/100gm BW i.p. saline injections for 7 successive days. DOX-treated group: received 0.1ml/100gm BW i.p. saline injections for 7 successive days, followed by a single i.p. injection of DOX, 20 mg/kg i.p. on the 7th day. ATX-treated group: received 40mg/kg/day BW i.p. ATX injections for 7 successive days. ATX+DOX treated group: received 40mg/kg/day BW i.p. ATX injections for 7 successive days, followed by a single i.p. injection of DOX, 20 mg/kg i.p. on the 7th day. At the end of the study, the overnight fasted rats were subjected to final arterial blood pressure measurement. Rats were then weighed and anaesthetized with 40 mg/kg B.W i.p. thiopental sodium. Then, ECG was recorded, blood samples were collected from abdominal aorta and centrifuged. The resulting plasma was used for measurement of plasma cardiac Troponin I (cTnI) and plasma Cytochrome C. The heart was subjected to In vitro study of isolated hearts perfused in langendorff preparation. Hearts and ventricles were weighed. The left ventricle was then stored at -80οC for later determination of cardiac tissue iron. Statistical Analysis was made using 1-way ANOVA for difference between means of different groups. Ethics Committee The study protocol was approved by the Research Ethical Committee of Faculty o fMedicine Ain Shams University (Reference No. FWA00017585). Results The systolic blood pressure was increased significantly in the DOX treated group compared to the control group. All of the systolic, diastolic and mean arterial blood pressures were significantly decreased in the ATX +DOX treated group compared to the DOX treated group. Heart rate was significantly increased in the ATX +DOX treated group compared to the control group, and compared to the DOX treated group. PT and PT/LVW were significantly increased in the ATX +DOX group compared to both of the DOX group and the control group. In addition, PT and PT/LVW were significantly increased in the ATX-treated group compared to the DOX group. The TPT was prolonged in the DOX group compared to the control group and this prolongation was statistically significant in pre-ischemia and 5 minutes after reperfusion of the isolated hearts, and was significantly shortened in the ATX-treated group and ATX +DOX group compared to the DOX. Also, TPT was significantly shortened in the ATX-treated and in the in the ATX +DOX groups compared to the control group. HRT was significantly prolonged in the DOX group compared to the control group. However, HRT was significantly shortened in the ATX-treated and ATX +DOX groups compared to the DOX group, and in the ATX +DOX group compared to the control group. The MFR and MFR/LVW were significantly decreased in the DOX group compared to the control group. However, the MFR was significantly increased in each of the ATX-treated group and ATX +DOX group when each was compared to the DOX group. Moreover, MFR was significantly increased in the ATX +DOX group compared to the control group. Each of plasma cardiac Troponin, plasma Cytochrome C and Cardiac Tissue Iron were significantly increased in the DOX group compared to the control group, and all were significantly decreased in the ATX-treated group when compared to DOX group, and in the ATX +DOX group when compared to the DOX group. No significant changes were detected in body weight, heart weights and ECG parameters between the different studied groups. Conclusion Doxorubicin produces acute cardiotoxic effects and impairs systolic and diastolic cardiac functions, which is due to increased oxidative stress, mitochondrial instability and iron accumulation in the cardiac tissue. Astaxanthin exerts a major cardioprotective activities against DOXinduced cardiotoxicity, probably due to its major antioxidant and iron chelation properties.

Cardioprotective Effect of Quercetin and Sitagliptin in Doxorubicin-Induced Cardiac Toxicity in Rats.

ObjectiveA previous study revealed a pronounced protective effect of combining quercetin (QC) with sitagliptin (STN) in testicular tissue. Accordingly, this study was designed to evaluate the cardioprotective effects of QC and STN each alone or in combination in doxorubicin (DOX)-induced cardiotoxicity in the rats.MethodologyThirty male adult Wistar rats were divided into five groups: the first group (control) treated with sodium chloride, the second group treated with DOX (3 mg/kg I.P. injection), the third group treated with DOX with a combination of QC (80 mg/kg), and STN (10 mg/kg), the fourth group treated with DOX and QC and the fifth group treated with DOX and STN. Blood was collected on day 22 and used for assessment of serum troponin, lactate dehydrogenase (LDH), creatine phosphokinase (CPK), total lipid profile, C-reactive protein (CRP), and total antioxidant capacity (TAOC). Atherogenic indices were also calculated. Cardiac tissue was sent for histopathological analysis.ResultsDOX produced a significant increase in the level of troponin, LDH, CKP, CRP, total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG), and atherogenic index of plasma; and significantly decreased TAOC. The combination of quercetin and sitagliptin was more effective than each treatment alone in restoring the level of troponin, LDH, CKP, CRP, Cholesterol, LDL, TG, atherogenic index of plasma and significantly increased TAOC compared to DOX treated group. The histopathological finding also supports the biochemical results.ConclusionThe study revealed the cardioprotective effects of the combination of QC and STN which could be attributed to the additive effects of this combination through antioxidant, anti-inflammatory, lipid lowering and anti-atherogenic activities; suggesting it as a good therapeutic candidate to be tested in the clinical setting.

Ferulic acid ameliorates doxorubicin-induced cardiac toxicity in rats.

Ferulic acid (FA) is a phenolic compound with potent antioxidant activity. The objective of the study was to study the protective effects of FA on doxorubicin (Dox)-induced myocardial toxicity in rats. Wistar rats received vehicle (control) or Dox (20 mg/kg, i.p.) or telmisartan (Tel; 10 mg/kg, p.o.) or ferulic acid (20 mg/kg and 40 mg/kg, p.o.) for 7 days followed by treatment with Dox (20) on the fifth day of treatment, except the control group. On day 8, electrocardiographic parameters were recorded followed by blood withdrawal and then the animals were sacrificed for histopathology. Administration of Dox showed prolonged RR, QTc interval, and QRS complex. The levels of serum CK-MB, LDH, IL-1β, and IL-6 were significantly increased (p < 0.01). Similarly, levels of Ca+2, Mg+2 ATPase, and Ca+2 ATPase and expression of ANP and BNP were significantly higher as compared to the control. In the FA-treated group, ECG was normal. The serum levels of CK-MB, LDH, IL-1β, and IL-6 were not elevated. Heart tissue Ca+2, Mg+2 ATPase, and Ca+2 ATPase did not show a statistical difference compared to the control group. The FA treatment attenuated the expression of ANP and BNP. FA (20 and 40) augmented myocardial GSH and Na+/K+ ATPase. Histopathology of the heart confirmed the cardioprotective effect of FA.

Octreotide protects doxorubicin-induced cardiac toxicity via regulating oxidative stress.

To explore the role of octreotide in doxorubicin-induced (DOX) cardiac toxicity in rats, and to investigate its underlying mechanism. A total of 24 male Sprague Dawley (SD) rats were randomly assigned into 3 groups, including: the control group (NS group), the DOX-induced cardiac toxicity group (DOX group) and the OCT pretreatment + DOX-induced cardiac toxicity group (OCT group). Each group had 8 experimental SD rats. Electrocardiogram was performed in each rat before and after animal procedure, respectively. The serum and heart samples of each rat were collected 10 days after the surgical procedure. Cardiomyocyte apoptosis in the myocardial ischemic area of rats was determined by hematoxylin and eosin (HE) staining and Terminal Deoxynucleotidyl Transferase dUTP Nick-end Labeling (TUNEL) staining. DOX-induced oxidative stress was evaluated by detecting the activities of SOD (superoxide dismutase), MDA (malondialdehyde), GSH (glutathione), T-AOC (total antioxidant capacity) and CAT (catalase). The expression levels of nuclear factor E2 related factor-2 (Nrf2), heme oxygenase-1 (HO-1) and quinone oxidoreductase 1 (NQO1) were detected by Western blot and immunohistochemistry. Compared with the NS group, heart rate and voltage of QRS wave were both significantly reduced in the DOX group, whereas Q-T interval was significantly prolonged (p < 0.05). Arrhythmia was even found in some rats of the DOX group. However, rats in the OCT group had significantly higher heart rate and voltage of QRS wave, as well as shorter Q-T interval when compared with those of the DOX group (p < 0.05). The levels of plasma CK-MB and LDH were remarkably lower in the OCT group than those of the DOX group. The activities of SOD, GSH, CAT and T-AOC in cardiac homogenate of the OCT group were higher than those of the DOX group. However, MDA activity and ROS level in cardiac homogenate were remarkably reduced in the OCT group when compared with those of the DOX group (p < 0.05). Cardiac pathological lesions were alleviated by OCT pretreatment. Moreover, the expression levels of Nrf2, HO-1 and NQO1 were significantly upregulated in the OCT group than those of the DOX group. Octreotide improves the anti-oxidant capacity of cardiomyocytes via activating the Nrf2 pathway, thereby protecting doxorubicin-induced cardiac toxicity in rats.

Cardioprotective effect of magnetic hydrogel nanocomposite loaded N,α-L-rhamnopyranosyl vincosamide isolated from Moringa oleifera leaves against doxorubicin-induced cardiac toxicity in rats: in vitro and in vivo studies

Cardioprotective effect of N, α-L-rhamnopyranosyl vincosamide (VR), isolated from the leaves of Moringa oleifera plant in doxorubicin (Dox)-induced cardiac toxicity rats was evaluated. Twelve (12) rats were randomly selected into three groups; two rats received distilled water in the control group, five rats in group I received varying concentration of VR treatment, and group II containing five rats received varying concentration of VR-loaded magnetic hydrogel nanocomposite. Malondialdehyde (MDA), glutathione peroxidase (GSH) and superoxide dismutase (SOD) enzymes activities level were analysed after two weeks. In addition, the expression of three heart failure markers; beta major histocompatibility complex (β-MHC), atrial natriuretic peptide (ANP), and B type natriuretic peptide (BNP) were also evaluated. It was observed that the level of these markers expression decreases with an increase in VR concentration (p < 0.05). The reduced GSH and SOD level were increased after VR administration, this extract also reduced the initially increased MDA level in cardiac tissue. Pharmacokinetic parameters evaluation showed that nanogel treated rats possesses a significantly increased VR plasma concentration, Cmax, Kel, t½(a), t½(el), Ka and AUC. The result of this study indicated that VR may help to lower the dosage level, and reduces the treatment course in cardiovascular diseases (CVD). Our conclusion proposes the cardio-protective ability of the isolated VR and its beneficial effect via free radical scavenging properties.

Protective effect of Sheng-Mai Yin, a traditional Chinese preparation, against doxorubicin-induced cardiac toxicity in rats.

BackgroundSheng-Mai Yin (SMY), a modern Chinese formula based on Traditional Chinese Medicine theory, has been used to treat cardiovascular diseases in Eastern Asia. Our study focuses on the cardioprotection of SMY against doxorubicin (DOX)-induced cardiac toxicity in vivo.MethodsRats were injected with DOX (2.5 mg/kg) in six injections over a 2-week period. SMY was administrated intragastrically at the dose of 8.35, 16.7 and 33.4 g/kg, or 16.7 g/kg only twice a day concurrently with DOX for the 2-weeks. A series of assays were performed to detect the effects of SMY on: (i) heart weight index (HWI) and left ventricular mass index (LVMI); (ii) cardiac function; (iii) heart tissue morphology; (iv) the contents of carboxy terminal propeptide of procollagen typeI (PICP), amino terminal propeptide of procollagen type III (PШNP), transforming growth factor-β1 (TGF-β1), B-type natriuretic peptide (BNP), monocyte chemoattractant protein-1 (MCP-1), interferon gamma (INF-γ) and interleukin 6 (IL-6) by ELISA; (v) the mRNA levels of TGF-β1 and toll-like receptor-2 (TLR2); and (vi) protein level of TGF-β1.ResultsRats treated with SMY displayed the reductions of BNP and CK-MB increased by DOX in a dose-dependent manner. Moderate dose of SMY exhibited the correction for the increased HWI, LVMI, and the injured cardiac function, as well as the collagen accumulation. In addition, cardioprotection of SMY against DOX-induced cardiac toxicity was demonstrated by the reduction of myocardial fibrosis, characterized by the suppression of PICP, PШNP and TGF-β1, as well as the anti-inflammation and the regulation for cardiac immune microenvironment, characterized by the inhibition of TLR2, MCP-1, INF-γ and IL-6.ConclusionsSMY may protect heart function through the restriction of myocardial fibrosis induced by DOX, which suggests the potentially therapeutic effect of SMY on DOX-induced cardiomyopathy.

Cardioprotective effects of curcumin and nebivolol against doxorubicin-induced cardiac toxicity in rats

Doxorubicin (DOX) is used in the treatment of cancer. However, cardiotoxicity is its major dose-limiting factor. Mechanism of DOX-cardiac toxicity is not completely elucidated. The aim of the current study was to explore whether the addition of subeffective dose of curcumin (100 mg/kg) to nebivolol would produce a better impact in treating DOX-induced cardiac toxicity in comparison with monotherapy. Male rats were used and subdivided into seven groups. Cardiac toxicity was induced in 6 groups by intraperitoneal injection of DOX over 23 days; of the six groups, five groups were treated with curcumin (100 and 200 mg/kg), nebivolol (1 and 2 mg/kg), and their combination; the sixth group was the control group used for comparison. Oral administration of curcumin and/or nebivolol attenuated DOX cardiotoxicity as manifested by increasing survival rate, improvement in body weight, heart index, and ECG parameters, increase in ventricular isoprenaline responses, and improvement in cardiac enzymes, oxidative stress, apoptosis, and histopathological picture. The addition of the current low subeffective dose of curcumin to nebivolol ameliorated DOX cardiac toxicity to a much greater extent than monotherapy showing better antioxidant and antiapoptotic effects versus the per se effect of nebivolol. Therefore, the current study encourages adding low dose of curcumin to potentiate the effect of nebivolol in the clinical management of cardiac toxicity improving the patients' quality of life if proper clinical safety data are available.

Cardioprotective effect of grape-seed proanthocyanidins on doxorubicin-induced cardiac toxicity in rats

Context: Doxorubicin (Dox) is an anthracycline antibiotic used as anticancer agent. However, its use is limited due to its cardiotoxicity which is mainly attributed to accumulation of reactive oxygen species.Objective: This study was conducted to assess whether the antioxidant, proanthocyanidins (Pro) can ameliorate Dox-induced cardiotoxicity in rats.Materials and methods: Male Sprague–Dawely rats were divided into four groups. Group I was control. Group II received Pro (70 mg/kg, orally) once daily for 10 days. Group III received doxorubicin 15 mg/kg i.p. as a single dose on the 7th day and Group IV animals were treated with Pro once daily for 10 days and Dox on the 7th day. The parameters of study were serum biomarkers, cardiac tissue antioxidant status, ECG, and effect on aconitine-induced cardiotoxicity.Results: Cardiac toxicity of doxorubicin was manifested as a significant increase in heart rate, elevation of the ST segment, prolongation of the QT interval and an increase in T wave amplitude. In addition, Dox enhanced aconitine-induced cardiotoxicity by a significant decrease in the aconitine dose producing ventricular tachycardia (VT). Administration of Pro significantly suppressed Dox-induced ECG changes and normalized the aconitine dose producing VT. The toxicity of Dox was also confirmed biochemically by significant elevation of serum CK-MB and LDH activities as well as myocardial MDA and GSH contents and decrease in serum catalase and myocardial SOD activities. Administration of Pro significantly suppressed these biochemical changes.Discussion and conclusion: These results suggest that proanthocyanidins might be a potential cardioprotective agent against Dox-induced cardiotoxicity due to its antioxidant properties.

Cardioprotective effect of methanolic extract of Ixora coccinea Linn. leaves on doxorubicin-induced cardiac toxicity in rats

Objectives:To investigate the effect of methanolic extract of Ixora coccinea Linn. (MEIC) leaves against doxorubicin-induced cardiac toxicity in rats.Material and Methods:Albino Wistar rats were pretreated with the methanolic extract of Ixora coccinea Linn. leaves (200 and 400 mg/kg, orally) for 1 week followed with the simultaneous treatment with doxorubicin (cumulative dose of 15 mg/kg in six divided doses for 2 weeks) along with the extracts for the next 14 days. On the 22nd day hemodynamic parameters such as blood pressure and ECG were recorded. Biochemical study including biomarkers like creatine kinase – MB (CK – MB), lactate dehydrogenase (LDH), SGOT and SGPT, tissue antioxidant markers viz. catalase (CAT), superoxide dismutase (SOD) and extent of lipid peroxidation viz. malondialdehyde (MDA) was estimated. Histopathology of heart was also done to assess the cardioprotective effect.Results:Pretreatment with MEIC significantly reduced (P<0.01) the ST segment elevation and also maintained the BP (P<0.01) close to normal. The MEIC significantly reduced the elevated level of biomarkers like CK - MB, LDH, SGOT, SGPT (P<0.01) near to normal, the MEIC also increased the tissue antioxidant markers viz. CAT, SOD and decreased the level of MDA (P<0.01) in cardiac tissue by dose-dependant manner. The histopathology of heart also further confirmed the cardioprotection provided by the methanolic extract of Ixora coccinea Linn. leaves.Conclusion:The results suggest a cardioprotective effect of Ixora coccinea Linn. leaves due to its antioxidant properties.

The protective effect of a purified extract of Withania somnifera against doxorubicin-induced cardiac toxicity in rats

The protective effect of a purified extract of Withania somnifera against doxorubicin-induced cardiac toxicity in rats

The protective effect of a purified extract of Withania somnifera against doxorubicin-induced cardiac toxicity in rats

The therapeutic value of doxorubicin as an effective antineoplastic agent is limited by its cardiotoxic side-effects. The administration of doxorubicin (10 mg/kg) to male Wistar rats induced necrosis and apoptosis in heart tissues. It also caused oxidative stress damage as evidenced by the elevation of malondialdehyde and protein carbonyl levels and catalase activity, accompanied by the concurrent depletion of total antioxidant capacity and of superoxide dismutase level in cardiac tissues. The doxorubicin-induced cardiotoxicity and oxidative stress damage were also accompanied by increases of myeloperoxidase activity, total calcium content, and the expression of Bcl-2 protein in heart tissues. Most of these doxorubicin-induced biochemical and histological alterations were effectively attenuated by prior administration of purified standardized extract (1.5% withanolides; manufactured by Idea Sphere Inc., American Fork, UT, USA) of Withania somnifera (300 mg/kg). Thus, Withania may play a role in the protection against cardiotoxicity and thus might be a useful adjuvant therapy where doxorubicin is the cancer-treating drug.