Available online on www.ijppr.com

International Journal of Pharmacognosy and Phytochemical Research 2016; 8(5); 848-864

ISSN: 0975-4873

Review Article

*Author for Correspondence

A Review on Protective Role of Phytoconstituents Against

Isoproterenol Induced Myocardial Necrosis

Raja. S*, Ramya. I, Ravindranadh. K

Department of pharmaceutical chemistry, GITAM Institute of Pharmacy, GITAM University, Andhrapradesh

Available Online: 1st May, 2016

ABSTRACT Heart disease remains the principal cause of death claiming millions of lives every year. Owing to technology and changes

in life style the myth of myocardial infarction primarily affecting elderly people has been busted with heart disease claiming

significant number of lives among young people also. Myocardial infarction occurs when a section of the heart is deprived

of oxygen leading to necrosis of the tissue. Isoproterenol induced myocardial necrosis came to light during the late fiftees.

Conventional drugs are likely to reduce mortality, but their general applicability is limited by problems with toxicity and

cost. Herbal medicine is used by more than one-fifth of the global population and it is an adept alternate to synthetic drugs.

The objective of current review is to assess the cardio protective potential of phyto constituents like alkaloids, organo

sulphur, carotenoids, flavonoids, glycosides, terpenoids, saponins and phenolic acid against isoproterenol induced

myocardial necrosis in rats. Pretreatment of rats with these phytoconstituents significantly prevented the deviated

biochemical variations such as marker enzymes, lipid profile and antioxidant parameters to near normal status. This review

article provides a comprehensive account of structure, dose and medical efficacy of cardio protective phytoconstituents.

Keywords: Cardioprotection, Isoproterenol, Myocardial infarction, Myocardial necrosis, Phytoconstituents.

INTRODUCTION

Human heart is a vital organ without which survival is next

to impossible. According to world health organistion data

16.7 million people die each year due to myocardial

infarction1. Myocardial infarction occurs when there is a

significant reduction or block in the blood supply to the

heart, leading to degenaration of a portion of the

myocardium. Necrosis of myocytes is the pathological

indication of myocardial infarction. Risk factors of

myocardial necrosis include diabetes, high blood pressure,

hypercholesterolemia, smoking, gender, age and sedentary

life style2.

Myocardial necrosis

During commonly encountered injuries like ischemia,

exposure to toxins, physical agents, chemical agents,

various infections, trauma etc the cell chooses necrosis as

the common pathway to cell death3. When myocytes are

exposed to these kinds of inherently damaging agents, it

culminates in cell death. The infarcted myocardium begins

to undergo coagulative necrosis between 4 and 12 h after

cell death. Morphological changes associated with

necrosis are loss of total nuclei, cytoplasmic cross-

striations and neutrophilic infiltration in first three days,

myocyte fragmentation in the first week and early

phagocytosis after the first week. In the second week the

granulation tissue progresses and evolves through

progressively dense collagen deposition and a scar is

completed by the second month4.

Isoproterenol induced myocardial necrosis

Soaring physical and mental stress can also root to

myocardial infarction and unexpected demise, supporting

a role for rise in catecholamines in myocardial infarction

pathophysiology5. Isoproterenol is a synthetic

catecholamine that has positive inotropic and chronotropic

effect. At therapeutic doses it increases cardiac output,

however when administered in large doses it was reported

to cause severe oxidative stress in the myocardium leading

to necrosis of the left ventricular heart muscle6.

Isoproterenol generates free radicals by the process of

autooxidation and this free radical mediated oxidative

stress was believed to be the mechanistic pathway via

which isoproterenol induced necrosis7. Free radicals

initiate and propagate a chain of reactions that attack

double bonds in membrane phospholipids yielding lipid

peroxidation products like malondialdehyde and

isoprostanes. When amino acids or proteins present in

enzymes are subjected to sulfhydryl mediated cross-

linking they undergo degeneration and lose their

enzymatic activity. Such a process is mediated by free

radicals leading to damage in mitochondrial membranes.

This consequently results in decreased synthesis of

adenosine tri phosphate (ATP). Deprivation of adenosine

tri phosphate in cells causes failure of membrane bound

ion pumps leading to cell swelling, and influx of calcium,

depletion of glycogen stores and reduction in protein

synthesis. Increased cytosolic calcium activates a series of

enzymes, like phospholipases mediated membrane

damage, endonucleases mediated chromatin

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IJPPR, Volume 8, Issue 5: May 2016 Page 849

fragmentation, and decrease in adenosine tri

phosphatases8. Free radicals stimulated the binding of

tumor necrosis factor (TNFR1) with death domain of

receptor-interacting protein causing cell necrosis9.

Concisely, free radicals induced myocardial necrosis

resulted in damage of mitochondria, cellular membranes,

DNA, disturbance in calcium homeostasis and misfolding

of proteins3. The most relevant mechanisms by which

isoproterenol causes myocardial necrosis are shown in

Graphical abstract 1.

Diagnostic tools of myocardial necrosis are (i) changes in

the electrocardiogram (ii) elevated serum enzymes such as

creatine phosphokinase(iii) elevated cardiac proteins like

troponin T or I (iv) decrease in antioxidant enzyme levels

and (v) pain similar to that of angina10. Conventional

treatment includes use of synthetic drugs like beta

blockers, anticoagulants, antithrombolytics, ACE

inhibitors and surgeries (cardiac catheterization,

angioplasty). However these drugs are associated with

limitations like side effects, cost, non availability,

resistance development etc. Since herbal derived drugs are

non toxic and eco friendly, these drugs must be given a

deep approach. Herbal treatments have been used in

people with congestive heart failure, renal failure and

myocardial necrosis11,12. Several poly herbal and herbo

mineral formulations are also useful in the treatment of

myocardial necrosis. Some of the plants which possess

myocardial activity are Allium sativum, Allium cepa,

Curcuma longaAsparagus racemosus, Caesalpinia

bonducella, Cassia fistula, Emblica officinalis etc13.

Literature survey showed as many as seventy

phytoconstituents obtained from plants that are

cardioprotective against isoproterenol induced myocardial

necrosis. This review summarizes the chemistry of active

metabolites and how they might fight against isoproterenol

induced necrosis and highlights their potential as novel

cardioprotectives. List of phytoconstituents, their dose and

mechanism by which they protect biochemical parameters

are given in Table1. The structure and IUPAC name of

phytoconstituents are listed in Table 2.

Phytoconstituents Proved to Be Protective Against

Isoproterenol Induced Myocardial Necrosis

Alliin

Alliin (S-allyl cysteine sulfoxide) is sulfur containing

compound present in Allium sativum (garlic)14. It is

composed of three units namely an allyl group, a sulfoxide

group and the non essential amino acid cysteine. γ-

glutamyl-S-allyl cysteine reacts with water molecules to

produce alliin. Compounds like allyl thio sulfinate, allicin,

allyl propenyl thiosulfinate, diallyl disulfide, and allyl

methyl sulfide are synthesized from alliin15. Studies were

carried out for the effective use of alliin in the treatment of

potassium dichromate induced renal injury. It exhibited

hypoglycemic effect by stimulating insulin production or

interfering with dietary glucose absorption16. It also

ameliorates the diabetic condition of alloxan treated rats.

Alliin is a potent antimicrobial and antifungal agent. Alliin

was evaluated for its preventive effect in isoproterenol

induced myocardial ischemia. It exerted potent cardio

protection by its anti oxidant and anti lipidaemic

properties17.

N-Acetyl cysteine (NAC)

N-acetyl cysteine is a organo sulphur compound found in

several vegetables, including garlic,shallots,bellpepper,

onion and pepper. It is the acetylated form of the amino

acid L-cysteine and essentially a prodrug that is converted

to cysteine by the enzyme amino acylase and absorbed into

the blood stream. The pharmacological activity of NAC is

credited to its sulfhydryl group18. It has potential as a

chemopreventive agent19 and is the choice for the

treatment of acetaminophen-induced hepatotoxicity20. It is

being successfully used to treat a variety of

neuropsychiatric and neurodegenerative disorders like

Alzheimer’s and Parkinson’s diseases and in the treatment

of human immune deficiency virus21. NAC stimulates

gastro-pulmonary vagal reflex and ciliary muscles by

which it clears the mucus from the airways. It inhibited

isoproterenol stimulated inflammatory factors (TNF-α, IL-

1β) thereby extending significant cardio-protective effect

against ISO induced myocardial injury in rats22.

Coptisine

Rhizoma coptidis contains coptisine, which is an

isoquinoline alkaloid. Other pharmacologically active

alkaloids present in the plant are berberine, palmatine and

epiberberine23. It exhibited a wide variety of beneficial

properties, including, anti-inflammatory, neuromodulatory

and antimicrobial activities24. A high dosage of coptisine

decreased the level of 3-Hydroxy-3-Methylglutaryl-CoA

reductase enzyme suggesting a critical role in anti-

hypercholesterolemia. Anti hepatoma and anti leukaemia

actions of coptisine have also been reported. Most

recently, studies showed that coptisine is a promising

candidate for prevention or improvement of diabetic

neuropathy and neuro degenerative disorders25. It

attenuated mitochondrial respiratory dysfunction,

suppresses expression of RhoA/ROCK (Rho-

associatedcoiled-coil forming protein kinase, ROCK) and

thereby exerted cardioprotective effect on isoproterenol

induced myocardial infarction in rats26.

Crocin

Crocin is a natural carotenoid found in the

flowers of Crocus sativus L, generally called as saffron

(Iridaceae family). It has two ester groups formed from the

sugar gentiobiose and the carboxylic acid crocetin. The

color of saffron is mainly due to crocin. Among the other

pharmacologically active constituents like picrocrocin and

safranal of Crocus sativus, crocin is the most important

and abundant antioxidant27. Crocin is water soluble

xanthophylls and was reported to show antidepressant

effect via the uptake inhibition of neurotransmitters28. In

organic dye-sensitized solar cells studies speculate that it

has the potential to be a good photosensitive agent.

Research reveals crocin as potent antinociceptive,

antiinflammatory, hepatoprotective and anticancer agent29.

A study showed that crocin has antioxidant effect in

ischemia-reperfusion models of stroke. In addition, crocin

exhibited cardioprotective effect in isoproterenol induced

cardiac toxicity. It restored endogenous antioxidants and

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IJPPR, Volume 8, Issue 5: May 2016 Page 850

lipid peroxides in such a way that maintained the redox

status of the cell30.

Cinnamic acid and cinnamic aldehyde

Cinnamic aldehyde and its derivative cinnamic acid are the

main chemical ingredients of Cinnamomum cassia. The

existence of a disubstituted carbon-carbon double bond in

the side chain of these chemicals gives rise to two different

stereo isomers, referred to as the cis (Z) and trans (E)

isomers. Experimental studies indicate that

cinnamaldehyde possesses hypoglycemic and

hypolipidemic effects in streptozotocin induced diabetic

rats31. Cinnamaldehyde has also shown

anthelmintic, antiviral and gastrointestinal activities.

Cinnamic acid possesses anti-tumor activity and reduces

melanin production, likely via inhibition of

tyrosinase32. Cinnamic acid and cinnamaldehyde has been

reported to have anti-oxidative, anti-inflammatory and

anti-nephrotoxicity properties33. Cinnamic acid and

cinnamic aldehyde reduced the serum levels of cardiac

marker enzymes, TNF-α and IL-6 and serum nitric oxide

level in isoproterenol induced acute myocardial ischemia

rats. This indicated their potential to be used as

cardiovascular drugs34.

Catalpol

The roots of Rehmannia gluti- nosa contain iridoid

glucoside called catalpol35. Iridoids are monoterpenes

which are sud divided into four classes namely iridoid

glycosides, non-glycosidic iridoids, secoiridoids and

bisiridoids. The cyclopenta-[c]pyran system is the

distinctive feature of iridoid glycoside36. Catalpol could

improve the endocrine function of the hypothalamic-

pituitary- adrenocortical-axis and alleviate the structural

damage of hypothalamus in Alzheimer's disease37. It also

provided protection against cerebral ischaemia/reperfusion

injury and lipopolysaccharide-induced acute lung injury38.

Studies showed hypoglycemic effect of catalpol in

streptozotocin-induced diabetic rats. Analgesic and

chemotherapeutic effect of catalpol were also reported. By

the activation of Notch1 signaling pathway catalpol

renders a protective effect on cardiotoxic rats39.

Calycosin and gallic acid

Calycosin and Gallic acid are obtained from the herb Radix

Astragali and Radix Paeoniae respectively. Radix

Astragali, of the family fabaceae contains various

isoflavones and isoflavonoids like calycosin-7-b-D-

glucoside, ononin, calycosin and formononetin40.

Calycosin suppressed breast cancer cell growth via

regulation of insulin like growth factor 1 receptor

pathways. It also possesses neuroprotective and anti-

hyperglycemic activities41. Calycosin has a protective

effect in endothelial cells against hypoxia-induced barrier

impairment. In isoproterenol induced myocardial necrosis

of rats, calycosin and gallic acid synergistically inhibited

the infiltration of neutrophils and maintained membrane

integrity42.

Carnosic acid

Carnosic acid is the major diterpene of rosemary plant-

Rosmarinus officinalis43. Rosemary has several

Auto oxidation--- release of o2 free radicals

.

Graphical Extract 1

Action point of phytoconstituents.

Impairment of oxidative

phosphorylation Attacks double bond in PUFA

NF-KB

Decrease in ATP

production

Increase in AMP

production

Failure of ATP dependent Na+, K+, ATPase.---

.Increase in Na

Increase in lipid peroxidation end

products

Acidosis, calcium

overload Cell damage

Cellular

swelling

Release of lysosomal and cardiac

enzymes in to extracellular fluid

Inflammatoy mediators TNFX, IL-6, IL-1B

Neutrophil infiltration

Inflammation

MYOCARDIAL

INFARCTION

MYOCARDIAL

NECROSIS

Isoproterenol (S.C)

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IJPPR, Volume 8, Issue 5: May 2016 Page 851

Table 1: Phytoconstituents protective against isoproterenol induced myocardial necrosis

Constitue

nts

Class Dose Effect of phytoconstituents on various

parameters

Mechanism Reference

Alliin Organo

sulphur

80,mg/kg

oral

Decrease in CK-MB, LDH, AST,

ALT, HMG CoA reductase.

Increase in LCAT

Lipid-lowering

effect.

Sangeetha and

darlin. 2007

N-

acetylcyst

eine

Organo

sulphur

10mg/kgoral Decrease in CK-MB, LDH, and TNF-

α, IL-1β.

Regulated pro-

inflammatory

factors

expressions.

Liu et al. 2009.

Coptisine Alkaloid 100mg/kg,

oral

Decrease in CK-MB, LDH, AST,

ALT.

Increase in SOD, CAT, GPT, GPX,

GSSH.

Strong

antioxidant

activity,

inhibited

RhoA/ROCK

expression.

Gong et al.2012

Crocin carotenoi

d

20 mg/kg,

oral

Decrease in Left ventricular end

diastolic pressure. Increase in

SOD, CAT.

Maintained

redox status of

cell,

antioxidant,antil

ipidaemic.

Goyal et al.2010

Cinnamic

acid &

Cinnamal

dehyde

Phenolic

acid

150 mg/kg,

oral

Decrease in creatine kinase, lactate

dehydrogenase, TNF-α, interleukin,

malondialdehyde.

Increase in Serum nitricoxide (NO)

level.

Anti-oxidative,

Anti-

inflammatory

properties and

by increasing

Nitric oxide

level.

Fansong et

al.2013

Catalpol Iridoid

glucoside

40 mg/kg,

oral

Decrease in LDH, CK-MB .Increase

in SOD.

Activation of

Notch1

signaling

pathway.

Jing Zeng et al.

2013.

Calycosin

and Gallic

acid

Flavonoid

, Phenolic

acid

40 mg/kg, i.p

&

8 mg/kg, i.p

Decrease in myeloperoxidase (MPO)

& malondialdehyde (MDA)

Increase in SOD, CAT, GPT, GPX,

GSSH.

Suppressed

neutrophil

infiltration and

prevented

myocardial

damage.

Cheng et

al.2015

Carnosic

acid

Polyphen

olic

diterpene

100 mg/kg,

oral

Decrease in Troponin I, CK-MB,

LDH, SGOT & SGPT. .

Increase in vitamin C & SOD, CAT,

GSH, GST, and GPX.

Enhanced the

nuclear

translocation of

Nrf2 and

upregulated the

phase

II/antioxidant

enzyme

activities.

Bidya et al.2014

Diosgenin Sapogeni

n

80mg/kg

oral

Decrease in CK-MB & β-

glucuronidase, β-N-acetyl

glucosaminidase, β-D- galactosidase,

Ca2+-ATPase, Mg2+-ATPase activity.

Increase in Na+/K+ ATPase.

Antioxidant and

membrane

stabilizing

potential.

Salimeh et

al.2011

Epicatech

in

Flavonoid

20mg/kg,

oral

Decrease in creatine kinase-MB,

troponin-T and lactate dehydrogenase

1 and 2- isoenzymes.

Increase in superoxide dismutase,

catalase, glutathione peroxidase.

Free radical

scavenging and

antioxidant

effects.

Prince. 2013

Epigallo

catechin

gallate

Flavonoid 30mg/kg

oral.

Decrease in Thiobarbituric acid

reactive substances, lipid

hydroperoxides.

Free radical

scavenging and

antioxidant

effects,

Devika and

Prince 2008.

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IJPPR, Volume 8, Issue 5: May 2016 Page 852

Increase in superoxide dismutase,

catalase, glutathione peroxidase, and

glutathione reductase and vitamin C,

vitamin E and ceruloplasmin

Ferulic

acid and

Ascorbic

acid

Phenolic

acid

20mg/kg

oral,

80mg/kg,

oral

Decrease in lipid peroxidation and

LDH, CPK, SGOT, and SGPT.

Increase in SOD, GPx, GST, CAT,

and GSH

Inhibite lipid

peroxidation,

Restoration of

antioxidant

status.

Yogeetha et al.

2006

Glycyrhiz

ic acid

Triterpene

saponin

glycoside

20 mg/kg, i.p Decrease in 8-isoprostane, necrosis,

hypertrophy, and nuclear pyknosis.

Increase in super oxide dismutase

and total glutathione, catalase,

reduced glutathione

Powerful

antioxidant and

reduced the

myocardial lipid

hydroperoxide

and 8-

isoprostane

level.

Haleagrahara et

al. 2011.

Kolaviron Flavonoid

200 mg/kg,

oral

Decrease in Creatine phosphokinase,

lactate dehydrogenase, alkaline

phosphatase, alanine

aminotransferase & aspartate

aminotransferase, malondialdehyde,

total cholesterol, triglycerides and

low-density lipoprotein.

Increase in superoxide dismutase,

catalase, glutathione S-transferase,

and reduced glutathione

Antioxidant. Adaramoye

and Lawal.

2015

Lycopene Carotenoi

d

10 mg/kg,

oral

Decrease in ST segment,

hemodynamic changes (i.e.systolic,

diastolic and mean arterial pressure),

myeloperoxidase and Caspase-3

protease activity.

Potent

antioxidant

activity.

Mohamadin et

al.2012

α

Mangosti

n

Xanthone 200mg/kg

oral

Decrease in b-D-glucuronidase, b-

D-galactosidase, b-D-N-acetyl

glucosaminidase, acid phosphatase

and cathepsin-D, TNF-a and COX-2.

Preserved the

myocardial

membrane

integrity and

extenuated

anomalous

TNF-α and

COX-2

expressions.

Devi and

Vijayaraghavan.

2007

Matrine Alkaloid 200

mg/kg,oral

Decrease in lactic dehydrogenase,

glutamic oxaloacetic transaminase

and creatine kinase, improved the left

ventricular (LV) dysfunction,

including increased lipid peroxidation

product malondialdehyde in plasma.

Increase in superoxide dismutase,

catalase and glutathione peroxidase.

Antioxidant

property.

Xiaobing et al.

2010

Morin Flavonoid

20 mg/kg,

oral

Decrease in creatine

phosphokinase, lactate

dehydrogenase, alkaline phosphatase,

alanine aminotransferase

Reduced lipid

peroxidation.

pogula et al.

2012

Marmesin

in

Furanoco

umarin

glycoside

200 mg/ kg

oral

Decrease in serum enzyme levels,

ST elevation lipidperoxidation and β-

glucuronidase.

Increase in R amplitude.

Membrane

stabilizing

action by

inhibiting the

release of β-

glucuronidase

from the

Vimal and

Devaki.2004

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IJPPR, Volume 8, Issue 5: May 2016 Page 853

diterpenoid constituents like rosmarinic acid, carnosol, and

carnosic acid. Over 80% of the antioxidant properties of

rosemary extract are predictably due to carnosic acid and

carnosol44. Carnosic acid was considered to be beneficial

in the prevention of chronic neurodegenerative diseases.

Kar et al45 illustrated the anti-proliferative and anti cancer

properties of carnosic acid. It is also endowed with

antimicrobial, anti-inflammatory and anti nephrotoxicity

properties46. Nuclear translocation of Nrf2 (nuclear factor

erythroid 2–related factor 2) and phase II/antioxidant

enzyme activities were increased in rats which are

pretreated with carnosic acid during isoproterenol induced

myocardial necrosis43.

Diosgenin

Dioscin which is found in yam (Dioscoreaspp.) is a

steroidal saponin with diosgenin as its aglycone. 2.7% of

dioscin and 0.004% of diosgenin is present in cultivated

yam, and 0.12-0.48% is present in wild yam47. Diosgenin

is a phytoestrogen that can be chemically changed into a

hormone called progesterone. It was used to make the first

birth control pills in the 1960. Diosgenin is a very useful

compound to control hyperlipidemia. It enhanced bone

development by increasing the production and secretion of

Type 1 collagen 48. It exhibited anticarcinogenic activity

and antiviral activity against hepatitis C virus

by significantly reducing the levels of viral ribonucleic

acid and viral proteins49. By its antioxidant property

diosgenin reversed the membrane-bound enzyme activity

and in doing so it maintained the normal electrolyte

concentration suggesting the protective action of diosgenin

in isoproterenol induced myocardial infarction50.

Epicatechin

(-) Epicatechin is a flavonoid isolated from the bark of

Pterocarpus marsupium,51. Unfermented cocoa beans

contain 120–180 g/kg of polyphenols with (−)-epicatechin

being the main polyphenolic compound approximating

subcellular

fractions.

Neferine Alkaloids 10 mg/kg,

oral

Decrease in Serum marker enzymes

and serum glycoprotein, lipid

peroxidation products.

Strong

antioxidant

property.

Gurusamy et al.

2013

Sinapic

acid

Phenolic

acid

12

mg/kg,oral

Decrease in cardiac hypertrophy, heart

cholesterol, triglycerides, free fatty

acids serum low density and very low

density lipoprotein cholesterol, ST-

segments.

Increase in high density lipoprotein

cholesterol

Anti

lipidaemic

effect

Roy and prince.

2013

Tannic

acid

Phenolic

acid

40 mg/kg, ip Decrease in marker enzymes and

tumor necrosis factor-α (TNF-α),

interleukin-1β (IL-1β),

Increase in endogenous anti oxidants

Antioxidant Hux et al. 2015

Vanillic

acid

Phenolic

acid

10 mg/kg,

oral

Decrease in Serum cardiac troponins,

and lipid peroxidation products,

interleukin-1β, interleukin-6 and

tumor necrosis factor-α, ST segments.

Increase in endogeneous antioxidants,

Antioxidant and

anti-

inflammatory

properties.

Stanely

Mainzen Prince

et al. 2011

Vincristin

e

Alkaloids 25µg /kg, i.p Decrease in creatine kinase-MB,

serum glutamate pyruvate

transaminase and lactate

dehydrogenase and troponin-T in the

serum, thiobarbituric acid reactive

substances and lipid hydroperoxides.

Increase in Superoxide dismutase,

catalase, glutathione peroxidase and

reduced glutathione, Na (+)/K (+)-

ATPase.

Mediated

through its free

radical

scavenging

property.

panda et al. 2014

Vincosam

ide

Alkaloids 40 mg/kg

oral

Decrease in troponin-T, creatine

kinase-MB, lactate dehydrogenase,

glutamate pyruvate transaminase, as

well as cardiac lipid peroxidation

Increase in Cellular antioxidants.

Free radical

scavenging

property.

panda et al. 2013

Zingerone Vanillyl

acetone

6 mg/kg,

oral

Decrease in Lactate dehydrogenase

isoenzymes 1 and 2 bands, plasma

lipid peroxidation products.

Increase in Nonenzymatic

antioxidant.

Antioxidant

effect, Anti

inflammatory.

Hemalatha and

Stanley. 2015

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IJPPR, Volume 8, Issue 5: May 2016 Page 854

Table 2: Structure and iupac name of phytoconstituents

Compound

name Structure IUPAC Name

Alliin

O

OHS

O

H2N

2 amino-3[(S)-prop-2-enylsulfinyl] propanoic acid.

N-acetyl

cysteine

O

OH

HS HN

O

(2R)-2-acetamido-3-sulfanylpropanoic acid.

Coptisine

N+

O

O

O

O

6,7-Dihydro-bis(1,3)benzodioxolo(5,6-a:4',5'-

g)quinolizinium.

Crocin

O

O

O

O

O

O

O

HO

HO

HO

HO

HO

HO OH

O

O

O

OH

OH

OH

OH

OH

OHHO

bis[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-

[[(2R,3R,4S,5S,6R)-3,4,5- trihydroxy-6-

(hydroxymethyl)oxan-2-yl]oxymethyl]oxan-2-

yl](2E,4E,6E,8E,10E,12E,14E)-2,6,11,15-

tetramethyl hexadeca-2,4,6,8,10,12,14-

heptaenedioate.

Cinnamic

aldehyde O

3-Phenyl-2-propenal.

Cinnamic acid

O

HO

3-Phenyl-2-propenoic acid.

Catalpol

O

HO

H

H

O

H

H

HO

HO

H

H

OH

H

OH

HHO

H

HO

O

(1aS,1bS,2S,5aR,6S,6aS)-6-Hydroxy-1a-

(hydroxymethyl)-1a,1b,2,5a,6,6a-

hexahydrooxireno[4,5]cyclopenta[1,2-c]pyran-2-yl

β-D-glucopyranoside.

Calycosin

O

O

O

OH

HO

7, 3’-dihydroxy-4'-methoxyisoflavone.

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Gallic acid

O

OH

HO

HO

HO

3, 4, 5-Trihydroxybenzoic acid.

Carnosic acid

O

HO

HO

HO

H

(4aR,10aS)-5, 6-dihydroxy-1, 1-dimethyl-7-propan-

2-yl-2, 3, 4, 9,10,10a-hexahydrophenanthrene-4a-

carboxylic acid.

Diosgenin

HO

O

O

CH3 H

H H

H

H3C

H

CH3

CH3

(3β,25R)-Spirost-5-en-3-ol.

Epicatechin O

OH

HO

HO

OH

OH

(2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-

chromene-3,5,7-triol.

Epigallo

catechin

Gallate

O

O

OH

HO

HO

O OH

OH

HO

OH

(2R,3R)-2-(3,4-Dihydroxyphenyl)-5,7-dihydroxy-

3,4-dihydro-2H-chromen-3-yl 3,4,5-

trihydroxybenzoate.

Ferulic acid

O

OHO

HO

4-Hydroxy-3-methoxycinnamic acid.

Glycyrrhizic

acid

O

HO

O

O

HO

O

OH

HO H3CH

H CH3

CH3

HCH3CH3

CH3

OH

HO

OH

OO

O

O

HO

(3b,20b)-20-Carboxy-11-oxo-30-norolean-12-en-3-

yl2-O-b-D-glucopyranuronosyl-a-D-gluco

pyranoside uronic acid.

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IJPPR, Volume 8, Issue 5: May 2016 Page 856

Kolaviron

OHO

OH O

OH

OHO

OH

OH

OR2

R1

O

GB-1 (R1-H,R2-H ),GB-2 (R1-OH,R2-H)

Kolaflavanone [garcinianin] R1-OHR2—Me

Lycopene

(6E,8E,10E,12E,14E,16E,18E,20E,22E,24E,26E)-

2,6,10,14,19,23,27,31-Octamethyl-

2,6,8,10,12,14,16,18,20,22,24,26,30-dotria

contatridecaen.

α-Mangostin

O

O

O

HO OH

OH

1,3,6-Trihydroxy-7-methoxy-2,8-bis(3-methylbut-

2-en-1-yl)-9H-xanthen-9-one.

Matrine

N

N

O

1H,5H,10H-Dipyrido[2,1-f:3',2',1'-

ij][1,6]naphthyridin-10-one.

Morin

O

O

OHHO

HO

OH

OH

3,5,7,2’,4’-pentahydroxyflavone.

Marmesinin

O OO

HO

CH3 O

HO

HO

OH

H

H

OH

H

CH3

H

2-[(2S)-7-Oxo-2,3-dihydro-7H-furo[3,2-g]chromen-

2-yl]-2-propanyl β-D-glucopyranoside.

Neferine

OH

O

N

O

O

N

O

O

4-[(6,7-Dimethoxy-2-methyl-1,2,3,4-tetrahydro-1-

isoquinolinyl)methyl]-2-{[6-methoxy-1-(4-

methoxybenzyl)-2-methyl-1,2,3,4-tetrahydro-7-

isoquinolinyl]oxy} phenol.

Sinapic acid

O

HO

O

O

OH

2E)-3-(4-hydroxy-3,5-dimethoxyphenyl)prop-2-

enoic acid.

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IJPPR, Volume 8, Issue 5: May 2016 Page 857

35%. Structurally, (−)-epicatechin is composed of two

phenyl rings linked by a chromene ring with a 4-hydroxyl

group. It decreased the liability of low density lipoprotein

to oxidation which prevents the initiation of

artherosclerosis52. Epicatechins are neuroprotective and

anti allergic. They inhibited prostate cancer cell

proliferation, potentially by suppressing androgen receptor

activation and androgen receptor-regulated gene

transcription53. Pretreatment with epicatechin prior to

exposure of gamma (γ) radiation prevented hepatic and

testicular damage. Given its antioxidant capacity, (−)-

epicatechin has been studied as a cardioprotective therapy.

Cardioprotection owing to free radical scavenging and

antioxidant effects, was observed when rats were

pretreated with (−)-epicatechin following stimulation of

myocardial infarction via isoproterenol injection54.

Epigallocatechin gallate (EGCG)

Epigallocatechin gallate is present in the leaves of

Camellia sinensis commonly called as green tea

leaves. (−)-Epigallocatechin gallate (EGCG), (−)-

Tannic acid

O

O

HO

HO

OH

HO OH

O

O

O O

O

O

O

OO

O

O

OH

OH

OH

O

O

OO

O

O

OH

OH

O

O

HO

OH

OH

OH

OH

OH

HO

OH

OHHO

HO

HO

OH

OH

OH

1,2,3,4,6-Pentakis-O-{3,4-dihydroxy-5-[(3,4,5-

trihydroxybenzoyl)oxy]benzoyl}-β-D-

glucopyranose.

Vanillic acid

4-hydroxy-3-methoxybenzoic acid.

Vincristine N

N

OH

CH3

N

N CH3

H O

CH3

O

O

O

HO

H3CO

OH3C

O

H3C

OH

methyl (1R,9R,10S,11R,12R,19R)-11-(acetyloxy)-

12-ethyl-4 [(13S,15S,17S)-17-ethyl-17-hydroxy-

13-(methoxycarbonyl)-1,11-

diazatetracyclo[13.3.1.0⁴,¹².0⁵,¹⁰]nonadeca-

(12),5,7,9-tetraen-13-yl]-8-formyl-10-hydroxy-5-

methoxy-8,16-

diazapentacyclo[10.6.1.0¹,⁹.0²,⁷.0¹⁶,¹⁹]nonadeca -

2,4,6,13-tetraene-10- carboxylate.

Vincosamide

N

OO

HO

OH

OH

N

O

OO

HO OH

HH

OH

O

OH

N,α-L-rhamnopyranosyl vincosamide.

Zingerone

O

O

HO

4-(4-Hydroxy-3-methoxyphenyl)-2-butanone.

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IJPPR, Volume 8, Issue 5: May 2016 Page 858

epigallocatechin, (−)-epicatechin gallate, and (−)-

epicatechin are some of the catechins present in this plant.

Epigallocatechin gallate (EGCG) constitutes a major

portion among all catechins available in green tea55. The

presence of a trihydroxy B-ring and a gallate group are

accountable for antioxidant activity of EGCG56.

Epidemiological and animal studies indicate that EGCG

showed protective activity in neurological disorders and in

cancer. EGCG is a potent inhibitor of many enzymes that

are involved in the fatty acid biosynthesis of plasmodium

falciparum, thus giving it an antimalarial effect57. Due to

its free radical scavenging and antioxidant effects; EGCG

manages the tissue defense system extending

cardioprotection to rats which suffer isoproterenol induced

myocardial infarction58.

Ferulic acid

Ferulic acid is one among the many ample phenolic acids

in plants and also present in high concentrations in foods

like navy bean, corn bran, wheat bran, eggplant, artichokes

and beets59. It can be found free, dimerized or esterified

with proteins and polysaccharides in the cell wall. Ferulic

acid contains an yellow liquid of cis isomer and a white

crystal of trans isomer, the latter corresponding to 90% of

its natural occurrence. Ferulic acid is a useful molecule for

antiviral therapy. It is a hepato protective agent against

toxins commonly ingested in the diet60. It also possesses

chemopreventive activity against colon cancer. Due to its

ability to stop radical chain reactions by resonance and

polymerization, ferulic acid offers protection against UV-

radiation. Ascorbic acid, is a naturally occurring water

soluble vitamin which has high antioxidant property.

Studies confirmed the protective role of a mixture of

antioxidants containing vitamin C, ferulic acid, and

phloretin on human skin from the harmful effects of

radioactive rays. When ferulic acid was given along with

ascorbic acid, they synergistically protected the

myocardium from oxidative stress by virtue of their lipid

peroxidation and antioxidant activities in rats61.

Glycyrrhizic acid

Glycyrrhizic acid is a triterpene saponin glycoside

obtained from the root of the plant GlyccyrhizaGlabra

(Liquorice), Leguminosae family62. It is a conjugate of

two molecules, namely glucuronic acid and glycyrrhetinic

acid. Liquorice contains more than 20 triterpenoids and

nearly 300 flavonoids. Among them, glycyrrhizin (GL),

18β-glycyrrhetinic acid (GA), liquiritigenin, licochalcone

A, and glabridin are the main active components63.

Glycyrrhizin is many times sweeter than sugar. Reports

demonstrate glycyrrhizic acid attenuated oxidative damage

caused by chemically induced liver damage in rats. In

many countries, viral hepatitis and dermatitis are treated

by using glycyrrhizic acid64. It is also known to have

activities against inflammation, ulcer, diabetis and

antiviral activities65. As it has high antioxidant activity and

could reduce cardiac lipid hydroperoxide and 8-

isoprostane level, gycyrrhizic acid treatment was found to

be efficient against isoproterenol induced acute myocardial

infarction in rats66.

Kolaviron

Kolaviron is a biflavonoid compound obtained from the

seeds of garcinia kola (family: Guttiferae) which is

commonly known as bitter kola. Kolaviron is the

predominant component in G. kola and it is a mixture of

biflavanones (GB1, GB2 and kolaflavanone)67. Many

studies have established the anti-inflammatory,

gastrointestinal and hepatotoxic activity of kolaviron in

animal models and in cell culture68. Kolaviron has been

reported to reduce the level of glucobe and cholesterol in

diabetic animals. By opening potassium channels and

preventing release of intracellular calcium, kolaviron

exerts vaso relaxant effects in smooth muscle69. Since

kolaviron was reported to elicit strong antioxidant activity,

the cardioprotective effects of kolaviron in rats intoxicated

with isoproterenol (ISO) was studied. Supplementation

with kolaviron caused significant elevation of cardiac

antioxidant enzymes, and reduced MDA levels70.

Lycopene

Lycopene is the major carotenoid present in tomatoes71.

Lycopene is a C40-carotenoid made up of eight isoprene

units; making it a tetraterpene. Lycopene cyclase catalyzes

the conversion of lycopene to β-carotene by substitution of

two β-rings at each end of the straight chain

carotene. This deep red color pigment has eleven

conjugated double bonds which are accountable for its

antioxidant activity72. Lycopene shows an array of

biological effects. It acts as a moderate hypocholestremic

agent, changes neurochemical defects, oxidative

imbalance, apoptosis and provides useful approach in the

treatment of neurodegenerative disease73. Anti

carcinogenic activities in liver, lungs, mammary gland and

skin of animal models were also reported74. Findings

exposed the cardioprotective property of lycophene against

isoproterenol induced oxidative stress and cardiotoxicity

in rats. These experimental activities are mediated by

means of antioxidant potency and free radical scavenging

activity of lycophene75.

α Mangostin

α-Mangostin is obtained from Garcinia

mangostana(family: Guttiferae). Many xanthones have

been extracted from leaves, whole fruit and heartwood.

The first among them is α-mangostin and was isolated in

1855. Other xanthones like γ-mangostin, gartanin, 8-

deoxygartanin, garcinone A, B, C, D and E are also

obtained from mangosteen-fruit. The reno protective effect

of α-Mangostin was evaluated by pérez-rojas et al76. . It

attenuated the neurotoxicity induced by amyloid beta Aβ-

(1-40) oligomers, suggesting the great potential of it to be

a candidate for Alzeimerdisease treatment. The

antibacterial, antifungal, antiplasmodial and anti

inflammatory activities were its early reports77. The

impact of α-Mangostin on lipid peroxidation during

myocardial infarction in rats induced by isoproterenol was

evaluated by devi and vijayaraghavan78. α-Mangostin

conserved the myocardial membrane integrity and

cotrolled deviating TNF-aα and COX-2 (cyclooxygenase-

2) factors by mitigating isoproterenol involved oxidative

stress and cellular damage efficiently.

Matrine

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IJPPR, Volume 8, Issue 5: May 2016 Page 859

Matrine is an alkaloid purified from dried roots of Sophora

flavescens Aiton (Leguminosae).The roots includes two

major tetracyclo- quinolizindine alkaloids (matrine and

oxymatrine) as its primary components79. Matrine has a

wide band of pharmacological actions including

antimicrobial, antiviral, antiinflammatory, antidiabetic, ,

antiobesity, neuroprotective and hepatoprotective

activities. Matrine was used for treatment of bacillary

dysentery, enteritis and malignant pleural effusion80.

Matrine prevented the proliferation of various types of

cancer cells chiefly through intervention of cell cycle

arrest81. The protective role of matrine on cardioprotection

against isoproterenol induced cardiotoxicity was exhibited

through its antioxidant property82.

Morin

Morin hydrate (morin) is a natural yellow crystalline

polyphenolic compound coming from branches of Morus

alba L (white mulberry) family: Moraceae. Providing

morin hydrate to immune cells had a positive

immunoprotective effect that showed its possible use in

inflammation related diseases83. Studies suggested morin

as a capable anti-virulence therapeutic agent for healing

Staphalococcus aureus infections84. A successful attempt

was made to study the effect of morin hydrate in

gentamicin induced nephrotoxicity. In addition, morin also

exerted various activities like, suppression of xanthine

oxidase, deterrence of oxidation of low-density

lipoprotein, immunomodulation,anticancer activity,

antioxidant and hypouricemic activities85. Morin rendered

cardioprotective benefits in isoproterenol induced

myocardial infarcted rats by regulating lipid metabolism86.

Marmesinin

Marmesinin is a linear furanocoumarin, found in spinous

tree Aegle marmelos which is commonly known as bael:

family Rutaceae. Active principles found in the leaves of

Aegle marmelose are rutin, b-sitosterol-b-glucoside and

marmesinin87. Administration of furano coumarin

prevented deoxyribonucleic acid from forming adducts in

various tissues of rats. It also increased the antioxidant

enzyme levels in liver and lung evidencing its radical

scavenging properties88. Pretreatment with marmesinin

inhibited the delivery of β-glucuronidase from the cellular

fractions in isoproterenol administered rats. This is done

by virtue of its stabilizing effect on membranes89.

Neferine

Neferine, is a bisbenzyl isoquinoline alkaloid extracted90

from the seeds of Nelumbo nucifera Gaertn (lotus). The

major phytochemicals present in lotus seeds are roemerine,

nelumbine, dauricine, liensinine, isoliensinine, lotusine,

nuciferine, and neferine. Of these, neferine is the major

isoquinoline alkaloid obtained, along with liensinine and

isoliensinine. Anticancer potential and anti-arrhythmic

action of neferine were reported earlier91. It also subdued

the increase of vascular smooth muscle cells and

significantly prevented bleomycin-induced pulmonary

fibrosis. Investigation of neferine against isoproterenol

induced myocardial infarction showed that it is a strong

antioxidant and can be used as a potent cardioprotective

agent against oxidative stress92.

Sinapic acid

Sinapic acid is a hydroxy cinnamic acid. Hydroxycinnamic

acids possess a phenylpropanoid C6-C3 structure and are

the main subgroup of phenolic acids with ubiquitous

distribution in the plant kingdom93. Sinapic acid exists in

both free and ester form. Citrus fruits hold diverse amounts

of sinapic acid, of which lemon (Citrus limonL.) has

maximum amount of 72.11μg/g and murcottorange (C.

reticulate, C. sinensis) has 50.1μg/g.94 (Neda et al,

2014). Sinapic acid has a potential and dose-dependent

anti mutagenicity character. It selectively kills the

pathogenic bacteria leaving beneficial lactic acid bacteria

alive. Anti hyperglycemic activity95 and neuroprotective

effects96 of sinapic acid were reported. Sinapic acid has the

potential to be used as a curative approach for inhibiting

hepatic inflammation. Its free radical scavenging ability,

membrane stabilizing features and antilipidaemic potential

could be the possible mode for its action against

myocardial infarction in rats caused by isoproterenol97.

Tannic acid

Tannic acid is a natural polyphenol, with a structure of

glucose molecule surrounded by hydroxyl groups with

gallicl acid98. Tannic acid is present in lentils, coffee, green

tea, red wine, chocolate etc99 (Chung et al, 1998). It’s safe

dosage ranges from 10 to 400 μg. Because of the presence

of many phenolic groups in tannic acid it has both

hydrophobic and hydrophilic features which are

accountable for its antioxidant activity100. It relieved skin

cancers caused by polycyclic aromatic hydrocarbon

carcinogens and lung cancer caused by N-methyl-N-

nitrosourea in mice. Anti-amyloidogenic activity and

antimicrobial properties were also successfully examined.

Recently the cardio defensive effects of tannic acid in

isoproterenol mediated myocardial Injury in rats was

carried out. It protected the myocardium by reducing the

over expression of apoptosis- connected proteins, activities

of biomarkers, and elevated the expression of

antioxidants101.

Vanillic acid

Vanilla beans has high amount of vanillic acid which is

obtained from oxidation of vanillin102. This dihydroxy

benzoic acid derivative has evolved into most prominent

food additive and is used in perfumes for its aroma.

Vanillic acid is one among the principal metabolites found

in people after drinking green tea103. It was moreover

found to be an inhibitor of snake toxin 5'-nucleotidase. It

possesses hepato protective, anti carcinogenicity,

antibacterial, antifilarial and antimicrobial properties104.

Studies showed that when isoproterenol induced

cardiotoxic rats were subjected to vanillic acid

pretreatment ,marked increase in myocardial function were

observed which is due to its free radical scavenging and

anti-inflammatory properties105.

Vincristine

Vincristine is a naturally occurring indole alkaloid present

in Catharanthus roseus. It is a medicinal plant (family

apocynacea), containing more than 100 diverse terpenoid

indole alkaloids106 out of which vinblastine (VLB) and

vincristine (VCR) are bis indole antitumor alkaloids. Their

monomeric precursor molecules are vindoline and

catharanthine respectively. Vinblastine and vincristine are

Raja et al. / A Review on Protective…

IJPPR, Volume 8, Issue 5: May 2016 Page 860

isolated from the leaves of the plant by techniques such as

tissue culture, cell culture, and shoot culture. Vincristine

exhibits potent pharmacological activities. It showed

antiparasitic effects against Trypanosoma cruzi 107. On

oxidation vinblastine is converted to vincristine which

arrests mitosis in metaphase. Vincristine is effectual for

treating wilkins’s tumour, acute lymphoblastic leukaemia,

hodgkin’s disease and neuroblastoma 108. Apart from this,

the cardio protective activity of vincristine in isoproterenol

mediated cardiac necrosis in rats has been evaluated and it

mediated the protective outcome by its free radical

scavenging property109.

Vincosamide

The leaves extract of Moringa oleifera Lam. generally

known as drumstick leaves (Family- Moringaceae)

contains an indole alkaloid called N, α-L-rhamnopyranosyl

vincosamide110. M. oleifera contains diverse

phytochemicals counting saponins, alkaloids, terpenoids,

flavonoids and phenolic acids. The leaves were reported

to show protection from radio-active rays and were

effective in thyroid and cancer treatments. Pretreatment of

rats with vincosamide considerably reduced the high level

of cardiac marker enzymes near to regular levels evidently

presenting the free radical scavenging property and

cardioprotective activity of this alkaloid110.

Zingerone

Zingerone is the least pungent component present in

Zingiber officinale, (family: Zingiberaceae). Zingerone is

primarily present in dry ginger 9.25% 111. Exposure to air

or heating converts gingerol into zingerone by retro aldol

process 112. Zingerone is known to have potent

pharmacological activities. Anti diarrhoeal, anti

inflammatory and anti cancer effects of zingerone were

studied extensively113. A possible mechanism responsible

for zingerone’s radio protective effect against X-rays,

gamma rays and infrared rays, was that it neutralized

radiation-induced reactive oxygen species and oxidative

stress by its strong antioxidant potential. Studies showed

that zingerone also has potent lipolytic activity 114.

Moreover Zingerone behaves as an appetite stimulant,

anxiolytic and antimicrobial agent. Recent studies

indicated that zingerone also safeguards the myocardium

against isoproterenol caused myocardial necrosis in rats by

virtue of its antioxidant effect115.

ABBREVIATIONS

ECG- Electrocardiography, GSH-Reduced Glutathione,

HDL-High density lipoprotein, MDA- Malondialdehyde,

TBARS- Thiobarbituric acid reactive substances, NF κB-

Nuclear factor kappa B, IL-6- Interleukin 6, TNF-α, -

Tumor necrosis factor alpha.

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