|Year : 2015 | Volume
| Issue : 1 | Page : 28-35
Cardioprotective effect of gallic acid against doxorubicin-induced myocardial toxicity in albino rats
JM Kulkarni, A. H. M. Viswanatha Swamy
Department of Pharmacology, KLEU's College of Pharmacy, Hubli, Karnataka, India
|Date of Web Publication||5-Jun-2015|
Dr. A. H. M. Viswanatha Swamy
Department of Pharmacology, KLEU's College of Pharmacy, Hubli - 580 031, Karnataka
Source of Support: None, Conflict of Interest: None
Objective: The present study was designed to investigate the protective and potential effect of gallic acid against doxorubicin (DOX) induced cardiotoxicity.
Materials and Methods: Adult Wistar albino rats of either sex weighing 150-200 g were used in this study. DOX administered intraperitoneally in six equal injections (each containing 2.5 mg/kg at 48 h intervals) to total cumulative doses of 15 mg/kg over a period of 2 weeks to induce cardiotoxicity. The estimation of cardiac and lipid biomarkers of both control and treated animals were observed. In vivo antioxidant parameters such as glutathione, superoxide dismutase, catalase, and malondialdehyde were also monitored. The remaining portion of the heart tissue used for histopathological studies.
Results: The treatment with doxorubicin increased the levels (P > 0.01) of serum cardiac and lipid biomarker which were brought down by gallic acid treatment. It also exhibited electrocardiographic changes such as reduced R wave and ST segment elevation. Histopathological study revealed that gallic acid restored the myocardial cells towards normal. The restoration of the endogenous antioxidant system clearly depicts that gallic acid have produced its protective effect by scavenging the reactive oxygen species.
Conclusion: The results of this study indicated that the cardioprotective effect of gallic acid might be attributed to its antioxidant property.
Keywords: Antioxidant, cardioprotective, doxorubicin, electrocardiography, gallic acid
|How to cite this article:|
Kulkarni J M, Swamy AV. Cardioprotective effect of gallic acid against doxorubicin-induced myocardial toxicity in albino rats. Indian J Health Sci Biomed Res 2015;8:28-35
|How to cite this URL:|
Kulkarni J M, Swamy AV. Cardioprotective effect of gallic acid against doxorubicin-induced myocardial toxicity in albino rats. Indian J Health Sci Biomed Res [serial online] 2015 [cited 2020 Jun 4];8:28-35. Available from: http://www.ijournalhs.org/text.asp?2015/8/1/28/158219
| Introduction|| |
Cardiotoxicity is a known side effect of numerous drugs which can be responsible for long term side effects lead to severe morbidity.  Cardiotoxicity includes a broad range of cardiac properties from little changes in various parameters such as blood pressure and arrhythmias to cardiomyopathy. There are several mechanisms of cardiomyopathy induced cardiotoxicity those includes cellular damage due to the formation of free oxygen radicals and stimulation of various immunogenic reactions in the presence of antigen presenting cells in the heart. 
The anthracycline drug doxorubicin (DOX) is one of the most effective antineoplastic agents, and widely used to treat a number of diseases has been restricted due to the dose-dependent cardiotoxicity and which may result myocardial damage, resulting in dilated cardiomyopathy with fetal congestive heart failure. 
The mechanism of DOX-induced cardiomyopathy is not completely understood, but several hypothesis have been postulated for the development of oxygen free radicals in the development of cardiomyopathy, this may be due to presence of semiquinone in the tetracycline aglycone molecule of DOX and it is reported to increase the generation of superoxide radicals and their damage the heart by exceeding detoxifying of cardiac mitochondrial tissues and sarcoplasmic reticulum. 
In earlier studies, it has been shown that antioxidant therapy is useful in the management of cardiotoxicity. In recent years, it is observed that growing interest in the usage of natural antioxidants as a protective strategy against the cardiovascular problems.  There are number of phytoconstituents from the various plants responsible for cardioprotective activity such as aloin (Aloe vera); alkaloids (Preema seratifolia); bromelian (Ananas comosus); some curcuminoides (Curcuma longa); embelicanin (Embelica officinalis); piperine (Piper longum); which possess antioxidant activity. ,,,,,
Gallic acid is a component of naturally occurring esters of gallotannins, which belongs to vary large group of plant polyphenols like gallotannins, these are found in legumes, vegetables, fruits and beverages.  Gallic acid is the hydrolyzed form of gallotannins. Chemically, gallic acid is 3, 4, 5-tryhydroxy benzoic acid. Gallic acid possesses strong free radical scavenging and antioxidant activity.  It has been also reported for antibacterial, antiviral, anti-inflammatory, ,,,, anticancer apoptotic actions. ,,
Oral treatment with gallic acid and quercetin alleviates lindane-induced cardiotoxicity in rats. Gallic acid prevents lysosomal damage in isoproterenol induced cardiotoxicity in Wistar rats  and also protects diabetes-induced myocardial dysfunction in rats. The effect of gallic acid on higher fat diet-induced dyslipidemia and oxidative stress in rats has been studied. , The present study is designed to investigate the protective effect of gallic acid against DOX induced cardiotoxicity.
| Materials and Methods|| |
All the chemicals used were of analytical grade.
Selection of animals
Male albino rats of Wistar strain weighing 150-200 g were procured from Venkateswara Enterprise. The animals were kept for 1-week in the animal house of KLEU's College of Pharmacy for acclimatization. The animals were housed in polypropylene cages and maintained at 27°C ± 2°C under 12 h light/dark cycle. They were fed with standard rat feed (Gold Mohur Lipton India Ltd.,) and water ad libitum was provided. Ethical clearance for the use of animals was obtained from the institutional animal ethics committee prior to the beginning of the project work.
In our study pretreatment, gallic acid was used at doses of 15 mg and 30 mg/kg body weight to assess the myocardial toxicity associated with DOX. The animals were divided into 6 groups of 10 animals each. Dosage of the DOX administered intraperitoneally was prepared in the saline (0.9% sodium chloride saline solution) in 6 equal injection (each dose containing 2.5 mg/kg, body weight) for a cumulative dose of 15 mg/kg body weight for the present study, were chosen based on previous reports. Preparation gallic acid suspension was prepared in 0.5% carboxyl methyl cellulose using distilled water. Dose of gallic acid 15 mg/kg and 30 mg/kg body weight were selected according to therapeutically equivalent dose.
Group I: Animal will be treated with vehicle alone, on the same regimen as DOX.
Group II: Animal will be treated with DOX (2.5 mg/kg body weight i.p) in 6 equal injections alternatively for 2 weeks to make a total cumulative dose of 15 mg/kg body weight.
Group III: Animal will be pretreated with gallic acid (15 mg/kg body weight p.o.) for 2 weeks and then alternatively with vehicle for next 2 weeks.
Group IV: Animal will be pretreated with gallic acid (15 mg/kg body weight p.o.) for 2 weeks) followed by DOX administration as in group 2.
Group V: Animal will be pretreated with gallic acid (30 mg/kg body weight p.o.) for 2 weeks) followed by DOX administration as in group 2.
Group VI: Animal will be pretreated with Vitamin E (100 mg/kg body weight p.o.) followed by DOX administration as in group 2.
After 36 h of the last treatment, orbital blood samples will be obtained under light ether anesthesia using heparinized microcapillaries for the estimation of cardiac biomarkers creatine phosphokinase and lactate dehydrogenase (LDH). Both control and treated animals were observed for as long as 3 weeks after the last injection for the general appearance, behavior, and mortality. At the end of 3-week posttreatment period, animals were sacrificed under ether anesthesia and a midline abdominal incision performed and heart tissue were quickly dissected out and were washed in ice-cold saline, dried on filter paper and weighed immediately.
A portion of each heart will be taken from all the groups and a 30% w/v homogenate were prepared in 0.9% buffered potassium chloride (pH 7.4) for the estimation of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA). Orbital blood samples were collected before sacrificing the animals and will be used for estimation of cholesterol, triglycerides and high-density lipoprotein (HDL). The remaining portions of the heart tissue were used for histopathological studies. A portion of the aorta will be taken and subjected it for the effect of gallic acid on intact and denuded endothelium of aorta preparation.
| Results|| |
The general appearance of all groups of animals was recorded throughout the study. In the later days, DOX treated animals developed alopecia, and the animal's fur became scruffy. These rats also had red exudates around the eyes and nose, soft watery feces and enlargement of the abdomen. These conditions were more severe at the end of study period. There were no deaths in the normal, gallic acid and Vitamin E control groups but a mortality rate of 60% was observed in DOX group while in gallic acid 15 mg/kg and gallic acid 30 mg/kg treated animals mortality was found to be 30% and 15% respectively. DOX treated group showed a decrease in their feed and water consumption during the drug treatment period as compared with the normal group. Control rats showed no significant changes in feed and water consumption as compared with normal. This consumption was improved in the treatment duration. In gallic acid-treated group, feed and water consumption was significantly increased as compared to DOX.
The body weight and body weight gain is gradually decreased in DOX treated group compared to the normal group while gallic acid treated group significantly increases the body weight gain as compared to DOX control group. Gallic acid control rats showed no significant changes in the body weight gain as compared with normal. In treatment group, that is, gallic acid (15 mg/kg) + DOX, gallic acid (30 mg/kg) + DOX and Vitamin E showed significantly increased (P < 0.05) (P > 0.001) and (P > 0.01) in the body weight gain as compared to DOX in the body weight gain [Figure 1]. In DOX-treated group, there was an increase in the heart weight, that is, 0.9899 ± 0.0098 g, whereas the value of the normal group is 0.7749 ± 0.0300 g. Gallic acid control rats showed no significant changes in the heart weight as compared with normal. The group treated with gallic acid (15 mg/kg) + DOX, gallic acid (30 mg/kg) DOX and Vitamin E was significantly reduced the heart weight to 0.8547 ± 0.0087, 0.7600 ± 0.3995 and 0.7554 ± 0.00365, respectively [Figure 2], when compared with DOX-treated group which is near to the normal. The ratio of heart weight to body weight in DOX-treated rats was significantly increased as compared with normal rats. The heart weight to body weight ratio in gallic acid control gallic acid (15 mg/kg) + DOX and rats was not significant as compared with normal rats. The ratio of heart weight to body weight in pretreatment group, that is, gallic acid (30 mg/kg) + DOX and Vitamin E is significantly (P < 0.05) decreased as compared with DOX rats.
|Figure 1: Effect of gallic acid on body weight in doxorubicin-induced myocardial toxicity in rats|
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|Figure 2: Effect of gallic acid on heart weight in doxorubicin-induced myocardial toxicity in rats|
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In DOX-treated group, there was an increase in the liver, kidney, and adrenal gland weight. Gallic acid control rats showed no significant changes in the liver, kidney, and adrenal gland weight as compared with normal. The group treated with gallic acid (15 mg/kg) + DOX, gallic acid (30 mg/kg) + DOX and Vitamin E was significantly reduced the liver, kidney and adrenal gland weight when compared with DOX treated group which is near to the normal [Figure 3], [Figure 4] and [Figure 5]. Rats administered with DOX shows a significant increase in the levels of creatine kinase-MB (CK-MB) and LDH as compared to normal. Gallic acid control rats showed not significant changes in the enzyme levels as compared with normal. The level of CK-MB and LDH in pretreatment group, that is, gallic acid (15 mg/kg) + DOX and gallic acid (30 mg/kg) + DOX and Vitamin E is significantly (P < 0.05), (P < 0.001) decreased as compared with DOX rats [Table 1].
|Figure 3: Effect of gallic acid on kidney weight in doxorubicin-induced myocardial toxicity in rats|
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|Figure 4: Effect of gallic acid on liver weight in doxorubicin-induced myocardial toxicity in rats|
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|Figure 5: Effect of gallic acid on adrenal gland weight in doxorubicin-induced myocardial toxicity in rats|
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|Table 1: Effect of GA on DOX induced changes in serum CK-MB, LDH cholesterol, and triglyceride and HDL levels in rats |
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Rats administered with DOX shows a significantly increased in the levels of cholesterol and triglyceride as compared to normal and there are slightly decreased in HDL levels as compared to normal group control gallic acid rats showed no significant changes in the cholesterol and triglyceride levels as compared to normal but there are significantly increased in the HDL level in gallic acid group compare to normal and DOX treated groups.
Effect of gallic acid on different electrocardiography (ECG) patterns: The study shows significant alteration of ECG patterns was observed in DOX administered rats as compared to normal control rats. The characteristic findings were the elevation of ST segment, reduction in P waves, QRS complex and decrease in heart rate. In addition, there was a prolongation of QT intervals. The consecutive loss of cellular membrane damage due to oxidative stress might be characterized by ST elevation. Pretreatment of gallic acid (15 mg/kg) and gallic acid (30 mg/kg) + DOX administration showed a protective effect against DOX induced altered ECG patterns and eliminated the acute fatal complication by protecting the cell membrane damage. Gallic acid (30 mg/kg) + DOX group shows more protective effect as compared with gallic acid (15 mg/kg) + DOX treated group.
The antioxidant enzyme levels in DOX treatment group showed a significant increase in lipid peroxidation (nmol MDA/min/mg of wet tissue) while a significant decrease in reduced GSH (nmol/min/mg of wet tissue), SOD (unit/mg protein) and CAT (unity/mg protein) when compared to normal group as given in [Table 2]. The histology of the heart tissue from control and treated rats showed normal morphological appearances. Where in Dox-treated group, disruption of loss of myofibrils and vacuolization of the cytoplasm were observed. The histology of heart tissues from the gallic acid treated groups showed less loss of myofibrils and vacuolization of the cytoplasm [Figure 6]a-g.
|Figure 6: Histopathological studies of various treated groups. (a) Normal (b and c) Dox treated (d) 15 mg GA ONLY (e) 15 mg GA+DOX (f) 30 mg GA+DOX (g) DOX+ VIT-E|
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|Table 2: Effect of GA on DOX induced changes in GSH, lipid peroxidation, CAT and SOD00 levels in heart of rats |
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| Discussion|| |
The present study was done to investigate the influence of gallic acid on DOX induced myocardial toxicity. Our results suggest that gallic acid prevents DOX induced cardiomyopathy in rats. Following lines of evidence can be emphasized from the present study. In the DOX treated group, the animal fur became scruffy, alopecia, and developed a pink tinge which in the later days of the observation period was followed by red exudates around the eyes and nose. Necrosis was also observed at the site of DOX injection. These changes were less pronounced in case of gallic acid 15 mg/kg + DOX, gallic acid 30 mg/kg + DOX and Vitamin E pretreated group. There was 60% mortality in DOX treated group, whereas in pretreated group of gallic acid15 mg/kg and 30 mg/kg there was 30% and 15% was found but no mortality was observed in gallic acid control and standard Vitamin E group. The DOX-treated rats showed an increase in heart weight and decrease in body weight. Decreased in the body weight may be due to the reduced intake of food. Increase in the heart weight may be attributed to the loss of myofibrils, dilation of sarcoplasmic reticulum, swelling of mitochondria, and increased number of lysosomes.  following this was the gross anatomical changes of the heart treated with DOX showed a typical chronic toxic response including cardiac hypertrophy, ventricular dilation and overall enlargement of the heart. This was determined by heart weight and ratio of heart weight: Body weight. However, all of the above changes were found to be inhibited in the preventive model of gallic acid 15 mg/kg + DOX and 30 mg/kg + DOX. The experimental study reveals severe biochemical changes as well as oxidative damage in the cardiac tissue after the chronic treatment with DOX (cumulative dose of 15 mg/kg body weight). DOX induced cardiotoxicity is due to destruct myocardial cells. As a result of this, CK-MB and LDH were released into the blood stream and serve as the diagnostic markers of myocardial tissue damage. , The amount of these cellular enzymes present in the blood reflects the alteration in plasma membrane integrity and/or permeability.
In the present study, DOX-treated rats showed a significant elevation in the levels of these diagnostic marker enzymes CK-MB, LDH. Moreover, elevated levels of these enzymes are an indicator of the severity of DOX induced myocardial damage, which is in line with an earlier report. , The prior administration of gallic acid 15 mg/kg + DOX and 30 mg/kg + DOX showed a significant reduction in DOX induced elevated serum marker enzymes. This reduction in the enzyme level confirms that gallic acid is responsible for maintenance of normal structural and architectural integrity of cardiac myocytes, thereby restricting the leakage of these enzymes, which can be accounted for membrane stabilizing property of gallic acid. Increased in the level of plasma triglycerides and total cholesterol in the DOX treated group indicate DOX may be interfering with metabolism or biosynthesis of lipids. The group which is treated with gallic acid has shown no significant increase in the lipid profiles such as total cholesterol, triglyceride when compared with the DOX treated group.
Pretreatment of gallic acid 15 mg/kg, gallic acid + DOX, 30 mg/kg + DOX and Vitamin E shown decrease in the lipid profiles and increase in HDL cholesterol when compared with the DOX treated group. This lipid-lowering effect of a gallic acid is due to inhibition of hepatic cholesterol biosynthesis, increased fecal bile acid secretion and stimulation of receptor-mediated catabolism of low-density lipoprotein (LDL), cholesterol. Decrease in the serum triglycerides, LDL-cholesterol, very low-density lipoprotein-cholesterol due to lipogenesis inhibiting effect of gallic acid.
Electrocardiograph abnormalities are the main criteria generally used for the definite diagnosis of myocardial injury. The study shows significant alteration of ECG patterns in DOX administered rats as compared to normal control rats. The characteristic findings were the elevation of ST segment, reduction in P waves, QRS complex and decrease in heart rate. In addition, there was a prolongation of QT interval. Moreover, ECG changes are an indicator of the severity of DOX induced myocardial damage, which is in line with an earlier report. , The consecutive loss of cellular membrane damage due to oxidative stress might be characterized by ST elevation. Pretreatment of gallic acid 15 mg/kg + DOX and 30 mg/kg + DOX administration showed a protective effect against DOX-induced altered ECG patterns and eliminated the acute fatal complication by protecting the cell membrane damage. DOX administration caused an increase in blood pressure, and Gallic acid pretreatment prevented the rise in blood pressure in the present study. The effect of DOX on blood pressure may also be due to catecholamine release.  In the different studies, it was shown that DOX administration result in increase or decrease in heart rate. , In our study, DOX decreased heart rate and, on the contrary, pretreatment with gallic acid is varyingly reduced the blood pressure induced by the DOX.
The mechanism of cardiotoxicity induced by a DOX is not clearly known from the present study, although large body of evidence supports that DOX administration is associated with a decrease in endogenous antioxidants and increase in oxygen free radicals resulting in increased oxidative stress, which is followed by development of a variety of subcellular changes in the myocardium, typical of DOX-induced cardiac injury.  In rat treated with DOX, we found a significant increase in heart tissue MDA levels suggesting increased lipid per oxidation and decreased in levels of GSH, SOD, and CAT. Cardiac tissue damage may be due to increased oxidative stress and depletion of antioxidants as reported earlier.  Gallic acid treatment might have scavenged the free radicals and hence increased levels of enzymatic and nonenzymatic antioxidants in the heart.  In this study, DOX-treated rats showed an increase in heart tissue MDA levels with a decrease in levels of GSH, SOD, and CAT, which confirms the oxidative stress and cardiac damage. Gallic acid prevented the DOX induced changes in MDA and enzyme levels. Significant increase in the GSH, SOD, and CAT activity and decrease in lipid peroxidation in heart tissue of gallic acid 15 mg/kg + DOX, gallic acid 30 mg/kg + DOX and Vitamin E treated groups was found.
Reactive oxygen species (ROS) are involved in the pathogenesis of DOX induced myocardial toxicity. Lipid peroxidation measured by thiobarbituric acid reactive substances has been generally accepted as an indicator of oxidative stress resulting from free radical over production and reduced antioxidant reserve  and play an important role in the pathogeneses of DOX induced cardiomyopathy. Lipid peroxidation involves the formation and propagation of lipid radicals, the uptake of oxygen and rearrangement of double bonds in unsaturated lipids which eventually results in the destruction of membrane lipids. The oxidation of biological membranes may cause impairment of membrane function, an increase of nonspecific permeability to ions leading to disruption of membrane structure.  The study also revealed a significant decrease in lipid peroxidation by gallic acid suggesting its protective effect.
The antioxidant enzymes SOD, CAT, and GSH play an important role in mitigating free radical-induced cell injury. In the heart, GSH is extremely important because of its ability to use and remove organic and inorganic peroxide.  Depletion of GSH in heart tissue of rats is known to result in enhanced lipid peroxidation which cause increased GSH consumption, as observed in the present study. The prior administration of gallic acid protects the myocytes against DOX induced myocardial toxicity by decreasing their susceptibility to free radicals. DOX induced decline in both SOD and CAT activity along with GSH contents promotes the formation of hydroxyl (OH) radicals, initiation and propagation of lipid peroxidation. The activities of antioxidant enzymes are in close relationship with the induction of lipid peroxidation, found in the present study. Reduced GSH is a major low molecular weight scavenger of free radicals in the cytoplasm and an important inhibitor of free radical mediated lipid peroxidation. It is commonly accepted that SOD protects against the free radical injury by converting O 2 -radical to H 2 O 2 and prevent the formation of OH-radicals through O 2 -driven Fenton reaction, and the H 2 O 2 can be removed by CAT. Administration of gallic acid, improved the antioxidant status and thereby preventing the damage to the heart, mainly because of the antioxidant sparing action of gallic acid so the antioxidant mechanism of gallic acid may include its well-known ingredients in Ayurveda possessing antioxidant activity which protect the cell from degenerative changes. Thus, in this work, gallic acid effectively prevented tissue damage by decreasing the oxidative stress and restoring the antioxidant status.
In the present study, DOX-treated groups failed to show the vasodilator effect this may due to vascular endothelial damage. This vascular damage is supported by vascular ROS production is elevated in different experimental models of hypertension. Increased O 2 -level is known to inactivate the vasodilator nitric oxide, leading to endothelial dysfunction, a characteristic feature of many vascular diseases, including hypertension. In various animal models of hypertension, an antioxidant SOD and SOD mimetics were found to lower the blood pressure suggesting that the oxidative inactivation of NO contributes to blood pressure elevation and in the present study the animals treated with gallic acid 15 mg/kg + DOX and gallic acid 30 mg/kg + DOX is effective in prevention of endothelial cell damage induced by DOX. 
In animals receiving DOX alone showed decreased effect on left ventricular pressure on isolated heart while the group treated gallic acid control group showed not much significant compared to normal. And gallic acid 15 mg/kg + DOX and 30 mg/kg + DOX showed similar changes in left ventricular pressure compared to normal animals. In animals receiving DOX, the inotropic responses were severely depressed, and there are no difference chronotropic responses as compared with the normal. Animals receiving gallic acid alone showed there is slight decrease in the chronotropic response while inotropic response was not much effected and the animals treated with gallic acid 15 mg + DOX, gallic acid 30 mg + DOX and Vitamin E both increased inotropic and chronotropic responses when compared to DOX these results depict that gallic acid treatment significantly ameliorated the cardiac damage induced by DOX. 
The vehicle-treated rats did not show any morphological changes and heart showed normal appearance. The cardiac muscle fibers were found to be of uniform size, shape, and configurations with no inflammatory cell infiltrates were present. Cardiomyopathy occurred in all rats injected with DOX, as illustrated by the appearance of enlarged, swollen mitochondria and vacuoles within the cytoplasm which is in line with an earlier report.  DOX produced massive change in the myocardium showing a varying degree of vacuolar changes in the cardiac muscle fibers mainly in the form of degeneration of myocardial tissue, vacuolization of the cardiomyocytes, infiltration of inflammatory cells and myofibrillar loss. Pretreatment with gallic acid 15 mg/kg + DOX and 30 mg/kg + DOX effectively inhibits DOX induced cardiac damage by the reversal of infiltration of inflammatory cells and fragmentation of myofibrils. Gallic acid protects DOX induced myocardial damage in the cardiac tissue of rats either by restoring endogenous antioxidant activity or as an antioxidant both. A similar action of scavenging of DOX induced free radicals by gallic acid in the present study cannot be ruled out. The data of the present study clearly showed gallic acid modulated most of the electrophysiological, biochemical, and histopathological [Figure 6]a-g parameters were maintained to near normal status in DOX-treated rats, suggesting the beneficial action of gallic acid as a cardioprotective agent.
| Conclusion|| |
The findings of the study suggests that the gallic acid protects against DOX-induced cardiotoxicity in rats as evidenced by improved mortality and effusion scores, mitigation of ECG abnormalities, improved cardiac injury markers, maintained the blood pressure and restoration of antioxidant status. Finally, we conclude that the cardiotoxicity induced by DOX is in a relationship with oxidative stress. Gallic acid has shown to be most effective in the functional recovery of the heart and restoration of biochemical and histopathological alteration which may be associated with its potent antioxidant property.
| Acknowledgment|| |
Authors are very much thankful to the Principal, KLEU's College of Pharmacy, Hubli for providing laboratory facilities.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2]
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