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Cardioprotective effect of Flavonoids, on lipid peroxides and antioxidants in isoproterenol induced myocardial infarcted rats

M. Pharm Dissertation Protocol Submitted to

Rajiv Gandhi University of Health Sciences, Karnataka

Bangalore– 560 041

By

Ms. RETTY PAUL E B.Pharm

Under the Guidance of

Dr. Divakar Goli M.Pharm. Ph.D

Professor

Department of Pharmacology,

Acharya & B.M.Reddy College of Pharmacy,

Soldevanahalli, Chikkabanavara (Post)

Hesaraghatta Main Road, Bangalore – 560 090

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

KARNATAKA, BANGALORE

ANNEXURE II

PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION

| | | |

| | |Ms. RETTY PAUL. E |

| | |EDAKKULATHUR HOUSE, |

|1. |Name of the candidate & |KAVALA, POTTA P.O |

| |Address. |THRISSUR |

| | |KERALA – 680 722 |

| | | |

| | |Acharya & B.M. Reddy College Of Pharmacy |

| | |Soldevanahalli, Hesaraghatta Road, |

|2. |Name of the Institution |Chikkabanavara Post, |

| | |Bangalore-560090. |

| | |Phone No: 080 65650815 |

| | |Fax No: 080 28393541 |

| | | |

|3. |Course of the study |M.Pharm (Pharmacology) |

| |& subject | |

| | | |

|4. |Date of admission |29th May-2008 |

| | |Cardioprotective effect of Flavonoids, on lipid peroxides and antioxidants in |

|5. |Title of the Topic |isoproterenol induced myocardial infarcted rats |

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|6. |Brief resume of intended work | |

| | | |

| |6.1 Need of the work |Enclosure I |

| | | |

| |6.2 Review of Literature |Enclosure II |

| | | |

| |6.3 Aim and Objective of the study |Enclosure III |

| 7. |Materials & Methods | |

| | | |

| |7.1 Source of data |Enclosure IV |

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| |7.2 Methods of collection of data |Enclosure V |

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| |7.3 Does the study require investigation on animals? | |

| |If yes give details |Enclosure VI |

| | | |

| |7.4 Has ethical clearance been obtained from your | |

| |institution in case of 7.3 | |

| | |Yes (Copy Enclosed) |

| | | |

|8. |List of references ( About 4 – 6) |Enclosure VII |

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|9. |Signature of the candidate | |

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|10. |Remarks of the guide | |

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|11. |Name & Designation of | |

| | |Dr. Divakar Goli M.Pharm. Ph.D |

| |11.1 Guide |Professor |

| | |Department of Pharmacology, |

| | |Acharya & B.M.Reddy College of Pharmacy, |

| | |Soldevanahalli, Chikkabanavara (Post) |

| | |Hesaraghatta Main Road , Bangalore – 560 090 |

| | | |

| |11.2 Signature of Guide | |

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| |11.3 Co – Guide |Mr. Manjunatha P. M. M.Pharm., (Ph. D) |

| | |Sr. Lecturer |

| | |Department of Pharmacology, |

| | |Acharya & B.M.Reddy College of Pharmacy, |

| | |Soldevanahalli, Chikkabanavara (Post) |

| | |Hesaraghatta Main Road , Bangalore – 560 090 |

| | | |

| |11.4 Signature of Co Guide | |

| | | |

| | | |

| | | |

| | | |

| | | |

| |11.5 Head of the Department |Dr. Kalyani Divakar M.Pharm. Ph.D |

| | |Professor & H.O.D |

| | |Department of Pharmacology, |

| | |Acharya & B.M.Reddy College of Pharmacy, |

| | |Soldevanahalli, Chikkabanavara (Post) |

| | |Hesaraghatta Main Road, Bangalore– 560 090 |

| | | |

| | | |

| |11.6 Signature of HOD | |

| | | |

| | | |

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| | | |

| | | |

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|12. |Remarks of the Principal | |

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| | | |

| | | |

| |Signature | |

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| | | |

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| | | |

| | |Dr. GOLI DIVAKAR. M Pharm PhD |

| | |Principal. |

| | | |

| | |Acharya & B.M.Reddy College of Pharmacy, |

| | |Soldevanahalli, Chikkabanavara (Post) |

| | |Hesaraghatta Main Road, Bangalore-560 090 |

Enclosure - I

6. BRIEF RESUME OF INTENDED WORK

6.1 NEED OF THE WORK:

Although clinical care is improved, public awareness is raised and health innovations are widely used, myocardial infarction remains the leading cause of death world wide [1]. It is the acute condition of myocardial necrosis that occurs as a result of imbalance between coronary blood supply and myocardial demand. Experimental and clinical studies have shown that there is increased generation of reactive oxygen species such as superoxide anion (.O-2) and hydroxyl radicals (.OH) in heart failure, which are involved in the formation of lipid peroxides, damage of cell membrane, and destruction of antioxidative defense system [2,3].

Isoproterenol (ISO), a synthetic catecholamine causes myocardial cell damage when administered in large doses. Mechanisms proposed to explain catecholamine-induced necrosis include an increase in cAMP levels, intracellular calcium overload and exhaustion of high-energy phosphates. Since catecholamines readily undergo oxidation, it has been suggested that oxidation products of catecholamines are responsible for myocardial changes observed following the administration of the parent compounds. There is strong evidence that adrenochromes and other oxidation metabolites of catecholamines can cause cell necrosis and contractile failure in rat heart. It is also known that auto-oxidation of catecholamines result in generation of highly cytotoxic free radicals. Therefore free radicals may play an important role in catecholamine-induced cardiotoxicity by causing peroxidation of membrane phospholipids, which can result in permeability changes in the membrane as well as intracellular calcium overload [4]. Isoproterenol induction also causes significant increase in the activities of acute serum myocardial injury marker enzymes (LDH, SGOT, CK-MB) [5].

The model of isoproterenol-induced myocardial ischemia is considered as one of the most widely used experimental model to study the beneficial effects of many drugs and cardiac function [6]. The pathological and morphological alterations in the heart of this non-coronary myocardial necrotic rat model are comparable with those taking place in human myocardial infarction [7].

Recently, attention has been focused on non-nutrient phytochemicals and polyphenols such as the flavonoids, alkaloids and xanthones which are derived from different plant species, the potential therapeutic agents of which is used in the prevention and management of cardiovascular diseases due to their antioxidant nature [8].

Hesperetin and Silymarin are two important medicinal constituents which are used for treatment of various ailments. The flavanone hesperetin is the major aglycone metabolite of hesperidin, abundantly found in citrus fruits. Hesperetin is known to act as an antioxidant and scavenger of peroxynitrite at low concentration [9,10]. Hesperetin was found to have neuroprotective, anti-inflammatory and antiproliferative effects [9,10,11]. Silymarin is a polyphenolic flavonoid extracted from the flowers and leaves of Silybum marianum (milk thistle) that has a strong antioxidant activity and exhibits cytoprotective, anti-inflammatory, and anti-carcinogenic effects and is used clinically to treat chronic inflammatory liver diseases and hepatic cirrhosis. Hepatoprotection can be attributed due to its antioxidant properties by scavenging free radicals and increasing intracellular concentration of glutathione [12]. Silymarin has a protective effect on the pancreatic damage in experimental Diabetes mellitus [13].

In our study, this noninvasive myocardial infarction rat model will be used to assess the efficacy of hesperetin and silymarin on protecting the heart against oxidative damage, and will focus on the correlate functional, biochemical, and histopathological changes.

Enclosure – II

2. REVIEW OF LITERATURE:

➢ In 2001 Kumar SHS et al studied about the cardioprotective effects of Picrorrhiza kurroa against isoproterenol-induced myocardial stress in rats. The cardioprotective effect of the ethanol extract of Picrorrhiza kurroa rhizomes and roots (PK) on isoproterenol- induced myocardial infarction in rats with PK (80 mg kg-1 day-1 for 15 days) significantly prevented the isoproterenol-induced myocardial infarction and maintained the rats at near normal status. The cardioprotective effect of PK is due to its free radical scavenging ability against IPL-induced lipid peroxidation, which is mainly responsible for the irreversible necrosis of the myocardial membrane or to its ability to inhibit the lipid accumulation in the myocardium by its hypolipidemic property [14].

➢ The study was aimed to evaluate the preventive role of isoproterenol (ISO)-induced myocardial infarction (MI) in rats and in vitro free radical scavenging assay. In myocardial necrosis induced by ISO showed a significant (P < 0.05) increase in the heart weight, blood glucose, serum uric acid, serum iron and a significant (P < 0.05) decrease in the levels of total proteins, albumin/globulin (A/G) ratio and iron binding capacity. A significant (P < 0.05) decrease in the activity of membrane bound enzymes such as sodium potassium dependent adenosine triphosphatase (Na+/K+ ATPase) and increase in the activities of calcium-dependent adenosine triphosphatase (Ca2+ ATPase) and magnesium dependent adenosine triphosphatase (Mg2+ ATPase) in the heart and a significant (P < 0.05) increase in the levels of glycoproteins in serum and heart. Pretreatment with naringin for a period of 56 days exhibited a significant (P < 0.05) effect and altered these biochemical parameters positively in ISO-induced rats. This shows that naringin has cardioprotective role in ISO-induced MI in rats [3].

➢ The study was conducted to elucidate the antioxidant role of garlic oil in isoproterenol (IPL)-induced myocardial infarction in rats. In myocardial necrosis induced by isoproterenol, a significant increase in serum iron content with a significant decrease in plasma iron binding capacity, ceruloplasmin activity and glutathione (GSH) level were observed. There was also a significant increase in lipid peroxidase (GPX), glutathione-S transferase (GST) and glutathione reductase (GRD) were decreased significantly in heart with isoproterenol-induced myocardial necrosis. Garlic oil produced a marked reversal of these metabolic changes related to myocardial infarction induced by isoproterenol. In conclusion, garlic oil exerts its effect by modulating lipid peroxidation and enhances antioxidant and detoxifying enzyme system [15].

➢ Panda VS et al investigated the protective effects of Ginkgo biloba Phytosomes (GBP) in isoproterenol (ISO)-induced cardiotoxicity and the antioxidant activity involved in this protection in rats. Levels of marker enzymes (AST, LDH and CPK) were assessed in serum and heart; antioxidant parameters viz., reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) and malondialdehde (MDA) were assayed in heart homogenate. Significant myocardial necrosis, depletion of endogenous antioxidants and increase in serum levels of marker enzymes were observed in ISO-treated animals when compared with the normal animals. GBP elicited a significant cardioprotective activity by lowering the levels of serum marker enzymes and lipid peroxidation and elevated the levels of GSH, SOD, CAT, GPx and GR. These studies have demonstrated that the cardioprotective effects of GBP in ISO-induced oxidative damage are due to an augmentation of the endogenous antioxidants and inhibition of lipid peroxidation of membrane [16].

➢ Isoproterenol induced myocardial infarction was confirmed by disturbances in serum and heart tissue marker enzymes such as lactate dehydrogenase (LDH), creatine phospho kinase (CPK), aspertate transaminase (AST) and alanine transaminase (ALT), increased level of lipid peroxidation and histopathological changes in the heart of isoproterenol administered rats. Pretreatment with mangiferin (10 mg/100 g body weight) for 28 days was found to ameliorate the effect of isoproterenol include pathological changes, reduced the lipid peroxide formation and retained the myocardial marker enzymes activities at near normal levels. The above results indicated the cardioprotective effect of mangiferin against isoproterenol induced myocardial infarction in rats [8].

➢ The study was designed to evaluate the cardioprotective potential of naringin on lipid peroxides, enzymatic and non-enzymatic antioxidants and histopathological findings in isoproterenol (ISO)-induced myocardial infarction (MI) in rats. Subcutaneous injection of ISO (85 mg/kg) to male wistar rats showed a significant increase in the levels of thiobarbituric acid reactive substances and lipid hydroperoxides in plasma and the heart and a significant decrease in the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione-S-transferase in the heart and the levels of reduced glutathione, vitamin C and vitamin E in plasma and heart and ceruloplasmin in plasma. Oral administration of naringin (10, 20 and 40 mg/kg, respectively) to ISO-induced rats daily for a period of 56 days showed a significant decrease in the levels of lipid peroxidative products and improved the antioxidant status by increasing the activities of antioxidant enzymes and non-enzymatic antioxidants. Histopathological findings of the myocardial tissue showed the protective role of naringin in ISO-induced rats. The results indicated that naringin possesses anti-lipoperoxidative and antioxidant activity in experimentally induced cardiac toxicity [17].

➢ The aim of this study was to analyze the effect of the flavonoid Silymarin, a free radical scavenger that prevents lipoperoxidation, on the pancreatic activity of super oxide dismutase (SOD), glutathione peroxidase (GSHPx) and catalase (CAT) in rats with alloxan-induced diabetes mellitus. Alloxan elicited an increase in the activity of the three enzymes, which decreased after 5 days of treatment. Silymarin also increased the activity of these enzymes. Simultaneous treatment with alloxan and Silymarin induced an increment in the activity of the enzymes followed by a delayed decrease (four doses) and a longer treatment with Silymarin (eight doses) induced a more sustained effect. Silymarin treatment recovered to control values for the activity of the three-antioxidant enzymes that were significantly diminished after 20 days of alloxan administration. The protective effect of Silymarin on pancreatic damage induced by alloxan may be due to an increase in the activity of antioxidant enzymes that, in addition to the glutathione system, constitute important defense mechanisms against damage by free radicals [18].

➢ Prabhu S et al analysed the protective role of mangiferin, a polyphenol from Mangifera indica Linn. (Anacardiaceae), on isoproterenol (ISPH)-induced myocardial infarction (MI) in rats through its antioxidative mechanism. Administration of ISPH caused myocardial damage in rat heart, which was determined by increased activity of serum lactate dehydrogenase (LDH) and creatine phospho kinase isoenzymes (CK-MB), increased uric acid level and reduced plasma iron binding capacity. The heart tissue antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione transferase and glutathione reductase activities), non-enzymic antioxidants (cerruloplasmin, Vitamin C, Vitamin E and glutathione levels) were altered in MI rats. Upon pretreatment with mangiferin to MI rats protected the above parameters to fall from the normal levels. Activities of heart tissue enzymic antioxidants and serum non-enzymic antioxidants levels rose significantly upon mangiferin administration as compared to ISPH-induced MI rats. This study concluded that mangiferin exerts a beneficial effect against ISPH induced MI due to its antioxidant potential, which regulated the tissues defence system against cardiac damage [4].

➢ Karthik M et al studied the preventive role of rutin on lipid peroxides and antioxidants in normal and isoproterenol-induced myocardial infarction in rats. Subcutaneous injection of isoproterenol (150 mg kg-1) to male wistar rats at an interval of 24 h for two days showed a significant increase in the activity of serum cardiac marker enzymes (CPK, LDH, AST and ALT) and a significant decrease in the activity of these enzymes in heart. Lipid peroxidative products (TBARS, lipid hydroperoxides) were significantly increased and enzymic (superoxide dismutase, catalase and glutathione peroxidase) and non-enzymic (reduced glutathione and vitamin C) antioxidants showed a significant decrease in isoproterenol-treated rats. Pretreatment with rutin (40 or 80 mg kg-1) to isoproterenol-treated rats orally for a period of 42 days daily caused a significant effect. Administration of rutin to normal rats did not have any significant effect on any of the parameters studied. The results of this study show that rutin possesses antioxidant activity in isoproterenol-induced experimental myocardial infarction [19].

Enclosure – III

6.3 AIM AND OBJECTIVE OF THE STUDY

AIM:

In the present study, different doses of hesperetin and silymarin will be tried to assess their cardioprotective effect in non-invasive myocardial infarction rat model.

OBJECTIVE:

To evaluate the cardiopotential of hesperetin and silymarin in non-invasive myocardial infarction injury induced by isoproterenol.

Enclosure – IV

7. Materials and Methods

7.1 SOURCE OF DATA:

The data will be collected from experiments on animals which involves the following:

1. Cardioprotective potential of hesperetin and silymarin

2. Evaluation of cardio protective activity of hesperetin and silymarin on experimental animals (male albino wistar rat).

Enclosure – V

7.2 METHOD OF COLLECTION OF DATA

a. Drugs and chemicals: Hesperetin, Silymarin and Isoproterenol (obtained from Sigma Chemicals)

b. Pharmacological studies:

Evaluation of cardioprotective activity of hesperetin and silymarin on experimental animals (male albino wistar rat) will be achieved by:

I Inclusion criteria: only healthy male wistar rats, weighing between 150-200 g shall be selected.

II Rats will be randomly divided into fifteen groups – each consisting of TWELVE animals.

Group 1: Sham group-Control group animals given saline (0.3 ml day-1/rat).

Group 2: Control group animals given vehicle (0.3 ml day-1/rat).

Group 3: Rats subcutaneously injected with isoproterenol (150 mg kg-1 day-1/rat dissolved in saline) once a day for 2 days.

Group 4: (low dose) Hesperetin given orally using an intragastric tube

daily for 42 days.

Group 5: (medium dose) Hesperetin given orally using an intragastric tube

daily for 42 days

Group 6: (high dose) Hesperetin given orally using an intragastric tube

daily for 42 days

Group 7: (low dose) Silymarin given orally using an intragastric tube daily for 42 days

Group 8: (medium dose) Silymarin given orally using an intragastric daily for 42 days

Group 9: (high dose) Silymarin given orally using an intragastric tube daily for 42 days

Group 10: Rats pretreated with (low dose) hesperetin given orally using an intragastric tube daily for 42 days and then subcutaneously injected with isoproterenol (150 mg kg-1 day-1/rat) once a day for 2 days.

Group 11: Rats pretreated with (medium dose) hesperetin given orally using an intragastric tube daily for 42 days and then subcutaneously injected with isoproterenol (150 mg kg-1

day-1/rat) once a day for 2 days.

Group 12: Rats pretreated with (high dose) hesperetin given orally using an intragastric tube daily for 42 days and then subcutaneously injected with isoproterenol (150 mg kg-1 day-1/rat) once a day for 2 days.

Group 13: Rats pretreated with (low dose) silymarin given orally using an intragastric tube daily for 42 days and then subcutaneously injected with isoproterenol (150 mg kg-1 day-1/rat) once a day for 2 days.

Group 14: Rats pretreated with (medium dose) silymarin given orally using an intragastric tube daily for 42 days and then subcutaneously injected with isoproterenol (150 mg kg-1 day-1/rat) once a day for 2 days.

Group 15: Rats pretreated with (high dose) silymarin given orally using an intragastric tube daily for 42 days and then subcutaneously injected with isoproterenol (150 mg kg-1 day-1/rat) once a day for 2 days.

Note- 180 animals are required for carrying out cardioprotective activity and after experiment 6 animals from each group will be sacrificed for collecting blood and heart tissue to carry out Bio-chemical estimations. Rest of the animals will be subjected to histopathological studies.

III Histopathological studies

IV Biochemical Estimation

Parameters selected for studying cardioprotective activity in tissue and serum.

a) Assay of creatinine kinase [19]

b) Assay of lactate dehydrogenase [19]

c) Assay of aspartate transaminase [19]

d) Assay of alanine transaminase [19]

e) Estimation of plasma TBARS [19]

f) Estimation of TBARS in heart [19]

g) Estimation of lipid hydroperoxides [19]

h) Assay of superoxide dismutase [19]

i) Assay of Catalase [19]

j) Assay of glutathione peroxidase [19]

k) Estimation of reduced glutathione [19]

l) Estimation of vitamin C [19]

m) Estimation of protein [16]

✓ The data obtained from the above study will be subjected to statistical analysis using ‘t’ test.

✓ Total duration for the completion of whole project may be 9 months.

I. Duration of experimentation Six months.

II. Literature survey one & half months.

III. Thesis writing one & half months.

ENCLOSURE – VI

7.3 Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please describe briefly.

The above study requires investigation on Albino Wistar Rats (male) for cardio protective activities.

7.4 Has ethical clearance been obtained from your institution in case of 7.3?

The study is cleared from Ethical Committee of the institution. (Certificate enclosed)

ENCLOSURE – VII

8. LIST OF REFERENCES:

.

1. Aronow WS. Epidemiology, pathophysiology, prognosis and treatment of systolic and diastolic heart failure. Cardiol 2006;14:108-24.

2. Biase D, Pignatelli P, Lenti L, Tocci G, Piccioni F. Enhanced TNF alpha and oxidative stress in patients with heart failure: effect of TNF alpha on platelet O-2 production. Thromb Haemost 2003;90:317-25.

3. Rajadurai M, Prince SM. Preventive effect of naringin on isoproterenol-induced cardiotoxicity in Wistar rats: an in vivo and in vitro study. Toxicology 2007;232:216-25.

4. Bhandari U, Ansari MN, Islam F. Cardioprotective effect of aqueous extract of Embelia ribes Burm fruits against isoproterenol-induced myocardial infarction in albino rats. Indian J Exp Biol 2008;46:35-40.

5. Zhou R, Xu Q, Zheng P, Yan L, Zheng J, Dai G. Cardioprotective effect of fluvastatin on isoproterenol-induced myocardial infarction in rat. Eur J Pharmacol 2008;586:244-50.

6. Grimm D, Elsner D, Schunkert H. Development of heart failure following isoproterenol administration in the rat: role of renin-angiotensin system. Cardiovas Res 1998;37:91-100.

7. Rona G. Catecholamine cardiotoxicity. J Mol Cell Cardiol 1985;17:291-300.

8. Prabhu S, Jainu M, Sabitha KE, Devi CSS. Cardioprotective effect of mangiferin on isoproterenol induced myocardial infarction in rats. Indian J Exp Biol 2006;44:209-15.

9. Smith SR, Schroetke LW, Bahia P, Fahmi A, Skilton R, Spencer JPE, Evans CR, Rattray M, Williams RJ. Neuroprotective effects of hesperetin in mouse primary neurons are independent of CREB activation. Neuroscience Letters 2008;438:29-33.

10. Cho J. Antioxidant and Neuroprotective Effects of Hesperidin and its Aglycone Hesperetin. Arch Pharm Res 2006;29(8):699-706.

11. Comalada M, Ballester I, Bailo´n E, Sierra S, Xaus J, Galvez J, Medina FS, Zarzuelo A. Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: Analysis of the structure–activity relationship. Biochem Pharmacol 2006; 72:1010-21.

12. Toklu HZ, Akbay TT, Ogunc AV, Ercan F, Gedik N, Uysal MK, Sener G. Silymarin, the Antioxidant Component of Silybum marianum, Prevents Sepsis-Induced Acute Lung and Brain Injury. J Surg Res 2008;145:214-22.

13. Soto CP, Perez BL, Favari LP, Reyes JL. Prevention of Alloxan-Induced Diabetes Mellitus in the Rat by Silymarin. Comp Biochem Physiol 1998:119C(2):125-9.

14. Kumar SHS, Anandan R, Devakib T, Kumar MS. Cardioprotective effects of Picrorrhiza kurroa against isoproterenol-induced myocardial stress in rats. Fitoterapia 2001;72Ž:402-5.

15. Saravanan G, Prakash J. Effect of garlic (Allium sativum) on lipid peroxidation in experimental myocardial infarction in rats. J Ethnopharmacol 2004;94: 155-8.

16. Panda VS, Naik SR. Cardioprotective activity of Ginkgo biloba Phytosomes in isoproterenol-induced myocardial necrosis in rats: A biochemical and histoarchitectural evaluation. Exp Toxicol Pathol 2008.

17. Rajadurai M, Prince SM. Preventive effect of naringin on lipid peroxides and antioxidants in isoproterenol-induced cardiotoxicity in Wistar rats: Biochemical and histopathological evidences. Toxicology 2006;228:259-68.

18. Sotoa C, Recobaa R, Alvareza C, Favarib L. Silymarin increases antioxidant enzymes in alloxan-induced diabetes in rat pancreas. Comp Biochem Physiol Part C 2003;136: 205–12.

19. Prabhu S, Jainu M, Sabitha KE, Devi CSS. Role of mangiferin on biochemical alterations and antioxidant status in isoproterenol-induced myocardial infarction in rats. J Ethnopharmacol 2006;107:126-33.

20. Karthik M, Prince SM. Protective role of rutin, a bioflavonoid, on lipid peroxides and antioxidants in isoproterenol-induced myocardial infarction in rats. J Pharm Pharmacol 2006;58:701-7.[pic]

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