Abstract

Iraqi J Pharm Sci, Vol.21(1) 2012 Protective effect of ginger extract

Protective Effect of Ginger Extract Against Cisplatin-Induced

Hepatotoxicity and Cardiotoxicity in Rats.
Ahmed M. Attyah* and Sajida H. Ismail*

*Department of Pharmacology and Toxicology,College of Pharmacy,University of Baghdad, Baghdad,Iraq.

Abstract
The protective effect of ginger extract against cisplatin-induced hepatotoxicity and

cardiotoxicity was evaluated in 30 albino white rats(weighing 200-300 gm ) classified into 5groups (6

rats per each group). The rats were treated with 0.5g/kg/day or 1g/kg/day ginger extract orally 5

successive days before and 5 successive days after induction of toxicity with intraperitoneal (IP)

injection of (10mg/kg ) cisplatin, resulted in a significant reduction in the levels of aspartate

aminotransferase (AST), alanine aminotransferase (ALT) , total serum billirubin(TSB) , lactate

dehydrogenase (LDH) and creatine kinase(CK) enzymes in comparison with the cisplatin treated

animals; ginger extract also improves the histological changes produced by cisplatin in the liver cells

and cardiac muscle fiber cells in comparison with the control . It is concluded that , ginger extract

when used concomitantly with cisplatin protects the liver and heart against the toxicity induced by this

cytotoxic drug.

Key wards :Ginger, Cisplatin,Oxidative Stress.

تأثيراث الحمايت لمستخلص الزوجبيل ضد التسمم الكبدي والقلبي المستحدث

بعقار السزبالتيه في الجرذان
احمد محمد عطيت* و ساجدة حسيه اسماعيل*

،1

ٔانسًٕو ، كهٛت انصٛذنت ، جايعت بغذاد ، بغذاد ، انعشاق األدٔٚت* فشع

الخالصة
بالحٍٛ زش انٕلائٙ انًحخًم نًادة يسخخهص انزَجبٛم ضذ انخهف انز٘ حسببّ يادة انسانخأثٛانٓذف يٍ ْزِ انذساست ْٕ حمٛٛى إٌ

جشراٌ( ٦خًست يجايٛع ٔنكم يجًٕعت ٔلسًج انٗ جشر يٍ انُٕع االيٓك٠٣)عضهت انمهب فٙ انجشراٌ خالٚا فٙ خالٚا انكبذ ٔ

نًذة خًست اٚاو نهجشراٌ يٍ خالل انفى ( ٕٚيٛا ى غى/كغ١ٔا غى/كغى٣٫٠) أظٓشث انُخائج اٌ اعطاء يادة يسخخهص انزَجبٛم ٔبجشعت

انٗ اَخفاض يعُٕ٘ بًسخٕٚاث رنك دٖأعٍ طشٚك انبشٚخٌٕ ( /كغىىيهغ١٣بالحٍٛ )زانسيٍ ٔاحذة جشعت اعطاء بعذخًست اٚاو لبم ٔ

. بالحٍٛ فمظزانسجشعت ب احى عالجٓ خٙانجشراٌ ان يجًٕعتيماسَت بًسخٕٚاحٓا عُذ ( , CK,TSB,AST ,ALT LDH) االَزًٚاث

حى عضهت انمهب نذٖ يجًٕعت انجشراٌ انخٙ خالٚا انزَجبٛم فٙ ححسٍٛ انخهف انحاصم فٙ َسٛج خالٚا انكبذ ٔ سخخهصيكزنك اسٓى

يٍ سخُخجا بالحٍٛ فمظ .ٔلذزجشعت انسحى عالجٓا ببالحٍٛ يماسَت بخهك انخٙ زجشعت يسخخهص انزَجبٛم لبم ٔبعذ جشعت انسعالجٓا ب

عضهت انمهب يٍ خالٚا بالحٍٛ لذ ٕٚفش انحًاٚت انكافٛت نُسٛج خالٚا انكبذ ٔزانس عماسيادة يسخخهص انزَجبٛم يع اٌ اسخعًال انذساست

.بالحٍٛزانخهف انز٘ ٚسببّ عماس انس

.جهد التأكسد السزبالتيه ، :الزوجبيل،الكلماث المفتاحيت

Introduction
Cisplatin is a platinum-based drug

(1)
,

which is one of the most effective anti-

neoplastic agents used for treatment of

testicular, ovarian, bladder, cervical, lung, and

neck cancers
(2)

. The cytotoxic effect of

cisplatin is believed to result mainly from its

interaction with DNA, via the formation of

covalent adducts between certain DNA bases

and the platinum compound
(3)

, despite its

clinical usefulness,cisplatin treatment has been

associated with several toxic side effects

including nephrotoxicity
(4)

, hepatotoxicity and

cardiotoxicity
(5)

. Cardiac events have been

reported in many case reports as well including

electro- cardiographic changes , arrhythmias ,

myocarditis, cardiomyopathy and congestive

heart failure
(3)

. It has been reported that

oxidative stress through the generation of

reactive oxygen species , decreases antioxidant

defense system including antioxidant enzymes

and non enzymatic molecules , reduced

glutathione, are major alterations in the

cisplatin toxicity
(6)

. Ginger belongs to a

tropical and sub-tropical family-Zingiberaceae,

it has been cultivated for thousands of years as

a spice and for medicinal purposes
(7)

. For

centuries, it has been an important ingredient in

Chinese, Ayurvedic and Tibb-Unani herbal

medicines for the treatment of rheumatism,

gingivitis, toothache, asthma , stroke, nausea,

vomiting and diabetes
(8)

. Extracts of the ginger

are rich in shagaols and gingerols which

exhibit anti-inflammatory , anti-oxidant and

anti-carcinogenic proprieties under ‘‘in vitro’’

and ‘‘in vivo’’systems
(9)

. This work was

designed to assess the protective effect of

orally administered ginger extract against

cisplatin-induced hepatotoxicity and

cardiotoxicity in rats .

1
Corresponding author E- mail : ph.sajida@yahoo.com

Received : 27/9/2011

Accepted : 18/12/2011

mailto:ph.sajida@yahoo.com

Iraqi J Pharm Sci, Vol.21(1) 2012 Protective effect of ginger extract

Materials and Methods
Preparation of Ethanolic Ginger Extract

The ethanolic extract of ginger was

made according to the method of Ajith et al.
(10)

by washing of fresh rhizomes of Zingiber

officinale several times with water. The 500 g

of rhizome was cut into small pieces and juice

was prepared in 70% ethanol. The extract was

prepared by heating the juice at 50–60
0
C for 24

hr with intermitted shaking , filtration made,

then centrifuge the extract at 2500g

,supernatant layer were pooled.The solvent was

evaporated completely at 50–60
0
C with the

help of rotary vacuum evaporator. The residue

thus obtained (6.5 g w/w) was used for this

study.

Animals and Experimental protocol

Thirty white Albino rats of both

sexes, weighing 200- 300 gm were used in this

study; they were obtained from and maintained

in the Animal House of the Pharmacy College,

University of Baghdad under conditions of

controlled temperature. The animals were fed

commercial pellets and tap water/ad libitum.

The animals were divided into five groups of

six animals and treated as follow: Group I-

received single IP dose of normal saline . The

animals were sacrificed after 5 days , this group

served as a negative control . Group II -

received single IP dose of cisplatin (10mg/kg)

and animals were sacrificed after 5 days, this

group served as positive control. Group III-

pretreated with oral dose of ginger extract alone

(1g/kg/day) and animals were sacrificed after

10 days . Group IV and V- animals pretreated

with oral dose of ginger extract (0.5g and 1g

/kg/day respectively) for 5 successive days

before and 5 successive days after single IP

cisplatin (10mg/kg) . Animals were sacrificed

after 10 days . Animals have been anesthetized

by ether, blood was collected directly from the

heart by (intracardiac puncture) and poured

into plain tubes , the clot was dispersed with

glass rod and then centrifuged at 3000 rpm for

15 minute ; the serum was used within 2 days

for the estimation of AST
(11 )

, ALT
(11 )

,TSB
( 12)

LDH
( 13)

and CK
( 14)

. Histological sections of

the hepatic and myocardial tissues were

prepared according to the method of Junqueira

LC. et al in 1995
( 15)

for evaluating the

histopathological changes with ordinary

microscope, using paraffin sections technique ,

tissues was cut into 3 millimeter pieces , fixed

in 10% formaldehyde solution , processed and

embedded in paraffin , blocks were cut by

microtome into 5micrometer ,thick sections ,

washed in water bath and left in the oven for

dewaxing ,then stained with haematoxyline and

eosin stain and then examined under light

microscope . The data presented as Mean+SD .

The significance of differences between the

mean values were calculated using unpaired

student's t-test. p -values less than 0.05 were

considered to be significantly different.

Results
Table (1) indicated that serum levels

of AST, ALT and TSB were significantly

elevated in the gp.II in comparison with the

gp.I (p<0.05). While in gp. IV and gp.V the

serum levels of AST, ALT and TSB were

significantly reduced , (fig.1,2&3). Histological

examination of tissue sections from the liver

showed certain degeneration and necrosis of

hepatocytes with inflammatory cells

infilteration around portal area with sinusoidal

dilatation were observed in the gp.II (fig.5).

While in gp.V the hepatic tissues was

protected against the cisplatin-induced damage

and shows normal liver tissues with no

significant degenerative changes when

compared with the gp.I liver tissue slide ( fig.

4&6).

Table 1 : The effect of ginger extract on the serum levels of AST, ALT and TSB of the treated

animals.

- Each value represents mean ± SD.

- * p < 0.05 in respect to the gp I .

- s = significant difference in respect to the gp II.

- N = number of animals

Ginger (1g/kg)

+ cisplatin

( Grp.V)

Ginger (0.5g /kg)

+ cisplatin

( Grp.IV)

Ginger (1g/kg)

alone

( Grp.. III)

Cisplatin

(10mg/kg)

( Grp.II)

Control

(Grp.I)

Groups

N=6/each group

8.5 ± 1.64
S

52.78 %

9.17 ± 1.94
S

49 %

5.33±1.37

18%

18± 2.28*

177 %
6.5± 1.05

Serum AST level (U/L)

and percent of change

5 ±1.41
S

50.84 %

5.17 ±1.17
S

49.1 %

3.67±1.37

18.4%

10.17 ± 2.99*

126 %
4.5± 0.55

Serum ALT level (U/L)

and percent of change

2.25 ± 0.21
S

63.4%

2.55 ± 0.15
S

58.5 %

1.38 ± 0.15

1.47%

6.15 ± 0.83*

352 %
1.36±0.29

TSB level (U/L)

and percent of change

Iraqi J Pharm Sci, Vol.21(1) 2012 Protective effect of ginger extract

Table(2) indicated that serum levels of LDH

and CK were significantly elevated in the gp.II

in comparison with the gp.I (p<0.05), While in

gp.IV and gp.V the serum levels of LDH and

CK were significantly reduced in comparison to

the gp.II (fig.7& 8).Histological examination of

tissue sections from the heart muscle clearly

showed degeneration and necrosis of cardiac

muscle fiber cells with fibrous tissue reaction

were observed in the gp.II (fig.10). While in

gp.V the cardiac tissues was protected against

cisplatin-induced damage and shows normal

tissue with no significant degenerative changes

when compared with the gp.I heart tissue slide (

fig. 9&11).

Table (2):The effect of ginger extract on the serum levels of LDH and CK of the treated animals.

- Each value represents mean ± SD.

- * p < 0.05 in respect to the gp I.

- s= significant difference in respect to the gp II.

- N = number of animals

Figure 1 : Effect of ginger extract on the serum

levels of aspartate aminotransferase (AST) in

rats with hepatotoxicity induced by cisplatin .

*P<0.05 in comparison with the gp I.

- s = significant difference in respect to the gp II.

Figure 2 : Effect of ginger extract on the serum

levels of alanine aminotransferase (ALT) in

rats with hepatotoxicity induced bycisplatin.

*P<0.05 compared with the gp l.

- s=significant difference in respect to the gp II.

Figure 3: Effect of ginger extract on the serum

levels of total serum billirubin (TSB) in rats

with hepatotoxicity induced by cisplatin

*P<0.05 compared with the gp I.

- s= significant difference in respect to the gp II.

Figure 4 : Section showing the normal liver

tissue of rats as control group. magnification

:100X , staining : haematoxylline &eosin.

Ginger (1g/kg)

+cisplatin

( Grp.V)

Ginger (0.5g /kg)

+ cisplatin

( Grp.IV)

Ginger (1g/kg)

alone

( Grp. III)

Cisplatin

(10mg/kg)

( Grp.II)

Control

(Grp.I)

Groups

N=6/each group

156 ± 30.2
S

43.37 %

176.7 ± 32.8
S

36 %

96.7 ± 14.5

1.86%

275.6 ± 29.26*

179.58 %

98.6± 18.04 Serum LDH level (U/L)

and percent of change

96.57 ± 3.59
S

35.13 %

128.71±7.93
S

13.54 %

75.73± 6.21

3.81%

148.87± 10.4*

89 %

78.73± 5.73 Serum CK level (U/L)

and percent of change

Iraqi J Pharm Sci, Vol.21(1) 2012 Protective effect of ginger extract

Figure 5 : Section showing morphological

alteration of liver tissue for cisplatin –treated

rats. Blue arraw represents hepatocyte

degeneration. Yellow arraw represents

hepatocyte necrosis. Red arraw represents

inflammatory cells infilteration around portal

area (white arraw ) . Green arraw represents

sinusoidal dilatation . magnification :200X,

staining :haematoxylline &eosin.

Figure 6: Section showing near normal

structural appearance of hepatocytes in gp Vby

administration 1g/kg/day

ginger extract against

cisplatin-induced liver damage. Blue arraw

represents normal hepatocyte.Yellow arraw

represents normal central vein.

Magnification : 200X, staining :haematoxylline

& eosin.

100

150

200

250

300

gp I gp II gp III gp IV gp V

LDH

levels(U/L)
*

s
s

Figure 7: Effect of ginger extract on the serum

levels of lactate dehydrogenase (LDH) in rats

with cardiotoxicity induced by cisplatin .

*P< 0.05 compared with the gp I.

- s= significant difference in respect to the gp II.

100

120

140

160

180

gp I gp II gp III gp IV gp V

CK Levels U/L

Figure 8 : Effect of ginger extract on the

serum levels of creatine kinase (CK) in rats

with cardiotoxicity induced by cisplatin .

*P<0.05 compared with the gp I.

- s= significant difference in respect to the gp II.

Figure 9: Section showing the normal cardiac

muscle fiber cells of rats as control group .

magnification :200X, staining :haematoxylline

&eosin.

Figure 10: Section showing morphological

alteration of cardiac muscle fiber cells from

cisplatin-treated rats( gp II). Yellow arraw

represents degeneration and necrosis of

myocardial fibers cells. Blue arraw represents

fibrous tissue reaction. magnification :200X,

staining : haematoxylline &eosin.

Iraqi J Pharm Sci, Vol.21(1) 2012 Protective effect of ginger extract

Figure 11 :Section of heart from rats treated

by ginger extract 1g/kg/day( gp V).

showing near normal like structure

appearance of cardiac muscle fiber cells

(Blue arraw). magnification : 200X, staining

:haematoxylline &eosin.

Discussion
The cytotoxic effect of Cisplatin is

enhanced by the elevation of the dose,

however,at higher doses, the less common toxic

effects, such as hepatotoxicity, may arise
(16)

.It

has been suggested that oxidative stress is an

important mechanism of cisplatin-induced

toxicity possibly due to depletion of reduced

glutathione GSH
(17)

, also many studies reported

that there were a significant elevation in the

hepatic malonaldehyde( MDA) and reduction

in the level of antioxidant enzymes in rats

treated with cisplatin
(18,19)

. Transaminases are

the most sensitive biomarkers directly

implicated in the extent of cellular damage and

toxicity because they are cytoplasmic in

location and are released into the circulation

after cellular damage
(20)

, elevation of the serum

levels of the hepatic enzymes and bilirubin are

the indicators for impaired liver functions
(21)

In this study,the hepatotoxicity of cisplatin was

clearly observed through an a significant

elevation of serum AST,ALTand TSB levels in

cisplatin-treated rats compared with the control

(fig.1,2&3) as it had been previously reported

that cisplatin administration causes

deteriorations of liver function tests such as

serum ALT, AST, LDH and TSB revealed

hepatic dysfunction, which could be a

secondary event following cisplatin-induced

liver damage with the consequent leakage from

hepatocytes
(19,21&22)

. Several reports
(23,10)

which

showed the protective effects of ginger extract

or its constituents, through their antioxidant

properties and improve the hepatic

dysfunctions and hepatic damage that induced

by hepatotoxicants, CCl4 and acetaminophen.

Results of this study demonstrated that ginger

extract improve the elevated levels of the serum

AST , ALT and TSB when compared to the

cisplatin treated group (p<0.05), and these may

be attributed to ginger components which may

stabilize hepatocytes plasma membrane and

prevent delivery of AST and ALT to the

extracellular fluid
(10)

. Histopathological

changes observed in the present study including

necrosis and degeneration of hepatocytes with

inflammatory cells infilteration around portal

area with sinusoidal dilatation ( fig.5) are

consistent in general with the other reports
(6,

24& 25)
, and these changes were nearly

normalized, when ginger extract in dose of

1g/kg/day
-
was co-administered with cisplatin

(fig. 6). In addition to antioxidant effects ,

ginger may also exert its hepatoprotective

effect by means of different ways. For example

, in the mechanism of cisplatin toxicity it was

shown that cisplatin induces liver cells

apoptosis by cytochrome-c release and caspase

3 release activation and causes hepatotoxicity

by increasing messenger ribonucleic acid(

mRNA) expression of nuclear factor-kappa B

(NF-ĸb) dependent cyclo-oxygenase (COX-II)

and inducible nitric oxide synthase (iNOS)
(26)

However, ginger shows anti-inflammatory

action by direct inhibition of COX activity
(27)

also exhibits greater inhibitory activity toward

the evolution of pro-inflammatory signaling

compound prostaglandin-E2( PG-E2) from

COX-II in lipopolysaccharide-activated

macrophages
(28)

, also Cisplatin hepatotoxicity

was shown to be exacerbated by elevated

expression of cytochrome P450-2E1

enzyme
(29)

, on the other hand Foster et al.

(2003) demonstrated that ginger components

showed significant inhibition of cytochrome

P450 mediated metabolism of marker

substrates
(30)

and also ginger prevents

bromobenzene-induced hepatotoxicity by

blocking the enzyme cytochrome P450-

2E1
(31)

.In this study ,the group administered a

single IP dose of cisplatin(10mg/kg) revealed

significant elevation of serum LDH and CK

levels compared to the control rats (fig.7&8),

are consistent with those observed in other

studies
(3,32)

which were reported that cisplatin-

induced cardiotoxicity could be a secondary

event following cisplatin-induced lipid

peroxidation of cardiac membranes with the

consequent increase in the leakage of LDH and

CK from cardiac myocytes . Concerning the

histological changes ,the cardiac damage

produced by cisplatin revealed degeneration

and necrosis of cardiac muscle fiber cells with

fibrous tissue reaction,(Fig.10), are consistent

in general with findings observed by Al-Majed

et al. in 2006 which showed degenerative

changes, vacuolated cytoplasm of many muscle

cells and blood vessels are engorged with

blood
(32)

.kidney damage induced by cisplatin

Iraqi J Pharm Sci, Vol.21(1) 2012 Protective effect of ginger extract

may lead to inhibition of carnitine synthesis

and also inhibition of carnitine reabsorption by

the proximal tubule of the nephron

consequently leading to carnitine deficiency .

This marked decrease (78%) of carnitine level

in cardiac tissue after treatment of cisplatin was

parallel to the marked increase in LDH and CK

and the degenerative changes in cardiac tissues,

which may point to the possible consideration

of carnitine deficiency as a risk factor in

cisplatin-induced cardiomyopathy
(32)

. cisplatin

elevates serum cardiotoxicity enzymatic indices

(LDH and CK) and causes severe

histopathological lesions in cardiac tissues,the

effect could be a secondary event following

cisplatin-induced lipid peroxidation of cardiac

membranes with the consequent increase in the

leakage of LDH and CK from cardiac myocytes
(32)

. There are many evidences deal with the

administration of antioxidants may be effective

in ameliorating cisplatin-induced

cardiotoxicity, acetyl-L-carnitine, DL-α-lipoic

acid and silymarin, which have been proven to

possess antioxidant potentials, appear to be

potential candidates to ameliorate

cardiotoxicity associated with cisplatin use in

rats
(33)

. The cardiac protection of ginger is very

well evident in this study, where increasing the

dose consequently reflected in better

protection; the reduction of serum enzymes

levels and reversing the histological changes

revealed by low incidence of degeneration and

necrosis in addition diminishing fibrous tissue

reaction as shown in figures 7,8&11.Mansour

et al. in 2008 showed that 6-gingerol act as

apotentially selective cardioprotective agent

, against cardiotoxicity induced by doxorubicin

by augmentation of endogenous myocardial

antioxidants activities
(33)

. The extent of

cardioprotection offered by ginger is associated

with a significant attenuation of serum LDH

,CK ,AST and ALT levels , a possible

explanation is that, ginger , via its effect against

lipid peroxidation, causes stabilization of

cardiac membranes and prevents the leakage of

cardiac enzymes, also may be due to

amelioration of renal functions and inhibition

of suppression of carnitine levels and

antioxidant enzymes such as catalase and

superoxide dismutase
(34)

.In conclusion

Oxidative stress plays a major role in cisplatin-

induced toxicities during the normal clinical

regimens of treatment. Antioxidants have

proven to be effective in ameliorating cisplatin-

induced toxicity in many preclinical and few

clinical interventions. Ginger extract is a

potent antioxidant which is reported to have

antitumor effect and to enhance the effect of

many known anticancer agents in addition to

reducing their toxicities as well.Ginger extract

prior and co-administration with cisplatin

provided near complete protection in terms of

plasma biochemical changes and organs

histological changes .

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