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J BIOCHEM MOLECULAR TOXICOLOGY
Volume 27, Number 12, 2013
Comparative Study of the Possible Protective Effects of
Cinnamic Acid and Cinnamaldehyde on
Cisplatin-Induced Nephrotoxicity in Rats
El-Sayed M. El-Sayed,1Ola M. Abd El-Raouf,2Hala M. Fawzy,2
and Mohamed F. Manie2
1Pharmacolgy and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Nasr-City, Cairo, Egypt;
E-mail: elsayed200_1956@hotmail.com
2Pharmacolgy Department, National Organization for Drug Control and Research, Cairo, Egypt
Received 29 April 2013; revised 21 June 2013; accepted 20 July 2013
ABSTRACT: This study aimed to assess the protec-
tive effect of cinnamic acid (CA) and cinnamaldehyde
(CD) against cisplatin-induced nephrotoxicity. A single
dose of cisplatin (5 mg/kg), injected intraperitoneally
to male rats, caused significant increases in serum
urea, creatinine levels, and lipid peroxides measured
as the malondialdehyde content of kidney, with signif-
icant decreases in serum albumin, reduced glutathione,
and the activity of antioxidant enzymes (catalase, su-
peroxide dismutase, and glutathione peroxidase) of
kidney as compared with the control group. On the
other hand, administration of CA (50 mg/kg, p.o.) or
CD (40 mg/kg, p.o.) for 7 days before cisplatin ame-
liorated the cisplatin-induced nephrotoxicity as indi-
cated by the restoration of kidney function and ox-
idative stress parameters. Furthermore, they reduced
the histopathological changes induced by cisplatin. In
conclusion, CA and CD showed protective effects
against cisplatin-induced nephrotoxicity where CD
was more effective than CA; affects that might be at-
tributed to their antioxidant activities. C2013 Wiley Pe-
riodicals, Inc. J. Biochem. Mol. Toxicol. 27:508–514, 2013;
View this article online at wileyonlinelibrary.com. DOI
10.1002/jbt.21515
KEYWORDS: Cinnamic Acid; Cinnamaldehyde; Anti-
Oxidant; Cisplatin; Nephrotoxicity
INTRODUCTION
Cisplatin (cis-diamminedichloroplatinum (II)) is
one of the most effective chemotherapeutic agents
Correspondence to: El-Sayed M. El-Sayed.
C2013 Wiley Periodicals, Inc.
widely used in the treatment of a variety of malig-
nancies, including head and neck, ovarian, and tes-
ticular cancers [1, 2]. However, the full clinical utility
of cisplatin is limited by its nephrotoxicity [3]. Ap-
proximately 28% to 36% of patients receiving an ini-
tial dose (50–100 mg/m2) of cisplatin develop acute
renal failure. The vigorous hydration has not been ef-
fective in eliminating cisplatin toxicity. Also, the use
of diuretics may complicate the electrolyte disturbance
induced by cisplatin. The discontinuation of cisplatin
remains the only option in cases of progressive renal
failure [4].
In addition to direct tubular toxicity in the form of
apoptosis and necrosis [5], vascular factors [6], and in-
flammation [7] that have been implicated in the patho-
genesis of cisplatin-mediated nephrotoxicity, several
other studies have also demonstrated that cisplatin-
induced oxidative stress is involved in the development
of renal tubule injury [8,9]. The involvement of oxida-
tive stress was further supported by the fact that free
radical scavengers and antioxidants prevent cisplatin-
induced nephrotoxicity [10–13].
Many antioxidant agents were investigated for
their preventive abilities against cisplatin-induced
nephrotoxicity. Some researches advised the use of en-
riched diets with natural antioxidants like vitamin E,
ascorbic acid, and methionine [14, 15]. Other studies
reported that the use of sulfhydryl-containing drugs,
such as captopril, diethyldithiocarbamate, sodium
thiosulfate, N-acetylcysteine, and lipoic acid, could also
exert antioxidant activity [16, 17].
Cinnamon, scientifically named Cinnamomum spp,
is a plant with many uses as a herbal medicine, con-
taining mucilage, tannin, sugar, resin, and essential
oil, among which the essential oil is the most impor-
tant part, a substantial portion of which is made up
508
Volume 27, Number 12, 2013 CINNAMON PREVENTS NEPHROTOXICITY 509
of cinnamaldehyde (CD) which possesses antioxidant,
antibacterial and anti-inflammatory effects [18, 19]. In
addition, cinnamic acid (CA), a major active phenolic
ingredient in cinnamon displays many pharmacolog-
ical properties, such as antioxidant and antimicrobial
activity [20, 21].
Therefore, the aim of this study was to assess
the possible protective effects of CA and CD against
cisplatin-induced nephrotoxicity in rats.
MATERIALS AND METHODS
Chemicals
Cisplatin was obtained from EIMC United Phar-
maceuticals, Egypt, and was given intraperitoneally
(i.p.) in a single dose of 5 mg/kg [22]. CA was ob-
tained from Qualikem Fine Chemicals (New Delhi, In-
dia), and was given orally in a dose of 50 mg/kg daily
for 7 days before the cisplatin injection [23, 24]. CD
was obtained from LLUCH Essence (Barcelona, Spain),
and was given orally in a dose of 40 mg/kg daily for
7 days before the cisplatin injection. CA and CD were
dissolved in dimethylsulphoxide 50% (DMSO), which
was obtained from Sigma–Aldrich Corporation (Lyon,
France). All other chemicals were of the highest analyt-
ical grades available commercially.
Animals
Male adult Sprague–Dawley rats weighing 230–
260 g were obtained from the breeding colony main-
tained at the animal house of the National Organiza-
tion for Drug Control and Research, Egypt. Animals
were caged in seven groups, given food and water ad
libitum and maintained at 21◦C–24◦C and 40%–60%
relative humidity with 12-h light–dark cycles. Animals
were subjected to an adaptation period of 2 weeks
in the animal house before experiments. The exper-
iments were conducted in accordance with the ethi-
cal guidelines for investigations in laboratory animals
and were approved by the Ethical Committee of Fac-
ulty of Pharmacy, Cairo University, Egypt, and com-
ply with the Guide for the Care and Use of Laboratory
Animals [25].
Experimental Design
Fifty-six male adult Sprague–Dawley rats were al-
located into seven groups (eight rats each); two rats
from each group were used for histopathological ex-
amination as follows:
Group 1: Received saline and served as control.
Group 2: Received DMSO 50% (as a solvent).
Group 3: Received CA in a dose of 50 mg/kg, p.o.
Group 4: Received CD in a dose of 40 mg/kg, p.o.
Group 5: Received cisplatin in a single dose of 5 mg/kg,
i.p.
Group 6: Pretreated with CA in a dose of 50 mg/kg,
p.o., for 7 days, followed by a single dose of cisplatin
(5 mg/kg, i.p.).
Group 7: Pretreated with CD in a dose of 40 mg/kg,
p.o., for 7 days, followed by a single dose of cisplatin
(5 mg/kg, i.p.).
Serum and Tissue Preparation
On the seventh day after the cisplatin injection,
blood samples were taken under light ether anesthe-
sia in nonheparinized tubes. Serum was separated by
centrifugation for 20 min at 4000×gand stored at
−20◦C.
The kidneys were rapidly isolated and washed
with ice-cold isotonic saline (0.9%). Then they were
stored at –80◦C till they were homogenized in 50 mM
phosphate buffer (pH 7.4) using an electronic homoge-
nizer (Ezister Daihan Scientific Company Ltd., Korea)
to prepare 10% w/v homogenate. The homogenate was
then made into aliquots and was used for the determi-
nation of kidney contents of malondialdehyde (MDA)
and reduced glutathione (GSH), and enzymatic activi-
ties of catalase (CAT), superoxide dismutase (SOD) and
glutathione peroxidase (GPx).
Biochemical Analysis
Serum urea nitrogen, creatinine, and albumin were
estimated colorimetrically according to methods of
Fawcettet and Scott [26], Bartles et al. [27], and Doumas
and Peters [28], respectively.
The kidney homogenate was used for the determi-
nation of thiobarbituricacid-reactive substances levels
measured as MDA according to the method of Satoh
[29], using 1,1,3,3-tetraethoxypropane as a standard.
Reduced GSH contents were assessed by the method
of Beutler et al. [30], using 5–5’ dithiobis (2-nitrobenzoic
acid) as a substrate. CAT activity was determined col-
orimetrically using hydrogen peroxide as a substrate
according to the method of Aebi [31]. SOD activity
was determined using the method of Nishikimi et al.
[32], which relies on the ability of the enzyme to in-
hibit the phenazinemethosulphate mediated-reduction
of nitrobluetetrazolium dye. GPx activity was mea-
sured by applying the method of Paglia and Valentine
[33] using hydrogen peroxide as a substrate.
J Biochem Molecular Toxicology DOI 10.1002/jbt
510 EL-SAYED ET AL. Volume 27, Number 12, 2013
TABL E 1. Effect of Pretreatment with CA or CD on Serum Urea, Creatinine, Albumin Levels, Final Body Weight, and Kidney–
Body Weight Ratio in Cisplatin-Treated Rats
Parameters
Groups Urea (mg/dl) Creatinine (mg/dl) Albumin (mg/dl) Final Body Weight (g) Kidney–Body Weight Ratio (1000×)
Control saline 25.37 ±2.11 0.48 ±0.04 4.29 ±0.19 235.30 ±3.99 5.60 ±0.11
DMSO 27.15 ±2.30 0.75 ±0.06 4.37 ±0.20 234.70 ±1.76 6.18 ±0.14
CA 25.25 ±2.22 0.74 ±0.06 4.28 ±0.09 243 ±6.23 6.22 ±0.12
CD 23.64 ±0.60 0.50 ±0.03 3.98 ±0.15 257.70 ±4.05 6.20 ±0.09
Cisplatin 127.10 ±0.79a4.98 ±0.34a1.37 ±0.06a202.2 ±1.83a11.3 ±0.17a
CA +cisplatin 69.27 ±3.83a,b0.74 ±0.05b3.68 ±0.15b249.30 ±9.45b9.35 ±0.19a,b
CD +cisplatin 46.91 ±1.06a,b,c0.77 ±0.03b4.07 ±0.15b256 ±6.01b7.13 ±0.24a,b,c
Data are expressed as means ±SEMofsixratspergroup.
aSignificantly different from the control saline group.
bSignificantly different from the cisplatin-treated group.
cSignificantly different from the CA +cisplatin-treated group using one-way ANOVA followed by the Tukey–Kramer test for multiple comparison test at p≤0.05.
Histopathological Examination
of the Kidney
Autopsy samples were taken from the kidney
of rats in different groups, and fixed in 10% neutral
buffered formalin for 24 h; and decalcification was car-
ried out on formic acid. Washing was done in tap water,
and then serial dilutions of alcohol (methyl, ethyl, and
absolute ethyl) were used for dehydration. Specimens
were cleared in xylene and embedded in paraffin at
56◦C in hot air oven for 24 h. Paraffin bees wax tis-
sue blocks were prepared for sectioning at 4 μm thick-
ness by sledge microtome. The obtained tissue sections
were collected on glass slides, deparaffinized, stained
by hematoxylin and eosin stain, and then examination
was done through the light electric microscope [34].
Statistical Analysis
All values were presented as means ±standard
error of the means (SEM). Statistical analysis was per-
formed using GraphPad Prism version 5 (GraphPad,
San Diego, CA). Comparison between different groups
was carried out using one-way analysis of variance
(ANOVA), followed by Tukey–Kramer’s multiple com-
parison tests. Difference was considered significant
when p≤0.05.
RESULTS
Table 1 shows that injection of cisplatin (i.p.) in
a single dose of 5 mg/kg caused significant increases
in serum urea (401%), creatinine (938%), and kidney–
body weight ratio (102%), and significant decreases in
body weight (14%) and serum albumin level (68%) after
7 days of treatment as compared with the control group.
Moreover, cisplatin (5 mg/kg) produced a signifi-
cant increase in MDA (124%) and significant decreases
in the GSH renal content (69%) and the enzymatic an-
tioxidant parameters in the kidney, that is, SOD, CAT,
and GPx (56%, 57%, and 77%, respectively, in compar-
ison with the control group) (Table 2).
In contrast, administration of CA for 7 days before
cisplatin significantly reduced the elevated levels of
urea and creatinine in serum by 46% and 85%, respec-
tively, as well as kidney–body weight ratio (17%), and
significantly increased the body weight (23%) and the
TABL E 2. Effect of Pretreatment With CA or CD on Kidney Contents of MDA and GSH as well as the Levels of Enzymatic
Antioxidants in Cisplatin-Treated Rats
Parameters
Groups MDA (nmol/g Tissue) GSH (mg/g Tissue) SOD (U/g Tissue) CAT (U/g Tissue) GPx (U/g Tissue)
Control saline 21.22 ±0.84 14.79 ±0.86 463.50 ±20.76 1.38 ±0.05 17.16 ±0.89
DMSO 23.74 ±0.16 13.63 ±0.64 395 ±16.86 1.39 ±0.08 13.05 ±0.73
CA 22.86 ±0.87 12.85 ±0.59 505.10 ±35.60 1.01 ±0.07 15.98 ±1.08
CD 19.68 ±0.69 14.04 ±2.22 385 ±13.88 0.88 ±0.03 11.78 ±1.80
Cisplatin 47.55 ±2.56a4.64 ±0.12a201.80 ±21.66a0.60 ±0.05a3.98 ±0.19a
CA +cisplatin 13.42 ±0.96a,b13.51 ±0.83b459.60 ±40.50b0.76 ±0.04a9.40 ±0.97a,b
CD +cisplatin 18.72 ±0.36b,c21.69 ±1.22a,b,c625.50 ±22.76a,b,c0.98 ±0.07a,b9.23 ±1.26a,b
Data are expressed as means ±SEMofsixratspergroup.
aSignificantly different from the control saline group.
bSignificantly different from the cisplatin-treated group.
cSignificantly different from the CA +cisplatin-treated group using one-way ANOVA followed by the Tukey–Kramer test for multiple comparison test at p≤0.05.
J Biochem Molecular Toxicology DOI 10.1002/jbt
Volume 27, Number 12, 2013 CINNAMON PREVENTS NEPHROTOXICITY 511
TABL E 3. Effect of Pretreatment with CA or CD on Histopathological Findings of Kidney Tissues of Cisplatin-Treated Rats.
Groups
Histopathological Control Cisplatin CD (40 mg/kg) +CA (50 mg/kg) +
Findings (Saline) (5 mg/kg) Cisplatin (5 mg/kg) Cisplatin (5 mg/kg)
Tubular cougulative necrosis 0 ++++ + ++
None Very severe Mild Moderate
Inflammatory cell infiltration 0 ++++ + ++
None Very severe Mild Moderate
Haemorrahage 0 ++++ + ++
None Very severe Mild Moderate
Renal casts 0 ++ + ++
None Moderate Mild Moderate
Tot al 0 14 ( +)4(+)8(+)
serum albumin level (169%) (in comparison with the
cisplatin-treated group). Furthermore, it decreased the
MDA content by 72% and increased GSH, SOD, CAT,
and GPx (191%, 128%, 27% and 136%) levels in kid-
ney tissue, respectively, in comparison with cisplatin-
treated group (Table 1 & 2). Similarly, treatment of an-
imals with CD (40 mg/kg) for 7 days before cisplatin
significantly reduced the elevated levels of urea and
creatinine in serum by 63% and 85%, respectively, as
well as kidney–body weight ratio (37%), and signifi-
cantly increased the body weight (27%) and the serum
albumin level (197%) (in comparison with the cisplatin-
treated group), while it decreased the MDA content by
61% and increased GSH, SOD, CAT, and GPx (367%,
FIGURE 1. Histology of kidney samples of the control (saline), cisplatin-treated group, CD +cisplatin-treated group, or CA +cisplatin-treated
group. (A) Control group: normal histological appearance of renal tubules (rt); (B) Cisplatin-treated group: inflammatory cells infiltration (m) in
between the cystic (s) and necrosed (n) tubules; (C) CD +Cisplatin-treated group: necrosis in some few individual tubules (n) with hyperplasia
and dysplasia in the lining epithelium (a) of other tubules; (D) CA +Cisplatin-treated group: degeneration and cystic (s) dilatation in most tubules
at the cortex. Hematoxylin–eosin staining, magnifications: ×40.
J Biochem Molecular Toxicology DOI 10.1002/jbt
512 EL-SAYED ET AL. Volume 27, Number 12, 2013
210%, 63%, and 132%, respectively) levels in kidney
tissue, in comparison with the cisplatin-treated group.
Histopathological findings of kidney tissues are
illustrated in Table 3 & Figure 1. The histopathological
examination of kidney sections of the control group
(saline) showed a normal histological structure
(Figure 1A). On the other hand, administration of
cisplatin to rats revealed degenerative changes, in-
flammatory cell infiltration between the cystic dilated
and necrosed tubules, and focal haemorrhage detected
in between the tubules at the corticomedullary junc-
tion (Figure 1B). Pretreatment of the rats with CD
(Figure 1C) or CA (Figure 1D) obviously mitigated the
histopathological changes induced by cisplatin.
DISCUSSION
Cisplatin is a major antineoplastic weapon used
for the treatment of solid tumors. Its chief dose-limiting
side effect is nephrotoxicity, which requires a reduction
of dose or discontinuation of the treatment [35].
The present study was designed to investi-
gate whether CA or CD administration before cis-
platin could afford protection against cisplatin-induced
nephrotoxicity.
Our results revealed that cisplatin produced sig-
nificant elevation in serum creatinine, urea levels, and
kidney–body weight ratio and a significant decrease
in the serum albumin level. The increased urea and
creatinine levels suggest the reduction of glomerular-
filtration rate [36]. Also, the increase in kidney–body
weight ratio could be attributed to the reduction of
body weight. Furthermore, cisplatin caused a signifi-
cant decline in the activity of the antioxidant enzymes
(CAT, SOD, and GPx), significant depletion of GSH,
and enhancement of MDA production in the renal tis-
sue. These findings are consistent with those of Ali et al.
[37], Fouad et al. [38] and Yadav et al. [39].
It was evident that cisplatin nephrotoxicity occurs
as a result of oxidative stress and increased genera-
tion of superoxide anion, hydrogen peroxide, and hy-
droxyl radicals due to the increased activity of NADPH
oxidase, xanthine oxidase, and adenosine deaminase
[13, 40]. These free radicals damage the lipid compo-
nents of the cell membrane via peroxidation and de-
naturing its proteins, which subsequently lead to en-
zymatic inactivation [41]. Moreover, cisplatin-induced
tubular damage could be explained by the fact that,
as fast as cisplatin is in the interior of the cells, the
hydrolysis product (chloride atoms replaced by water
molecules) reacts with GSH in the cytoplasm and DNA
in the nucleus [42]. The produced cisplatin-DNA in-
trastrand cross-links result in cytotoxicity (apoptosis/
necrosis) [43].
The present study demonstrated that pretreatment
with CA or CD ameliorated cisplatin-induced alter-
ations in serum creatinine, urea and albumin levels,
and body weight and kidney–body weight ratio. In ad-
dition, CA or CD significantly mitigated the lipid per-
oxidation in the rat kidney induced by cisplatin as man-
ifested by the decreased MDA level, accompanied by
the increased GSH content and enhanced activities of
CAT, SOD, and GPx. These results could be attributed
to the potential antioxidant effect of CA [44] and CD
[19], and are in agreement with those obtained by Pa-
tra et al. [45] who demonstrated that CA protects mice
from cyclophosphamide-induced hepatotoxicity and
myelotoxicity. Moreover, our results are consistent with
Molania et al. [19] who revealed the promising pro-
tective effect of CD against gamma radiation-induced
mucositis.
The histopathological findings demonstrated that
administration of cisplatin induced various degenera-
tive changes in kidney cells, which confirmed the bio-
chemical evidence of the oxidative stress. In contrast,
pretreatment with CA or CD obviously mitigated the
histopathological changes induced by cisplatin.
Our data showed that as a nephroprotective, CD
was more effective than CA. This could be explained
by the fact that a major portion of CD is metabo-
lized into CA and a portion of the absorbed CD conju-
gates with blood proteins before entering the liver, and
most of these protein conjugates escape hepatic first-
pass metabolism and slowly regenerate CD. Thus, this
whole process maintains CD concentrations in blood
for a long period [46].
In conclusion, CA or CD protected the kidney tis-
sue against cisplatin-induced nephrotoxicity in rats,
where CD was more effective than CA. The antioxidant
activities might be considered the main factors respon-
sible for such nephroprotective effects. Therefore, CA
or CD represents a potential candidate to prevent re-
nal injury, which is a major and dose-limiting problem
during the cisplatin therapy.
ACKNOWLEDGMENT
We thank Professor Dr. Adel B. Kholoussy, De-
partment of Pathology, Faculty of Veterinary Medicine,
Cairo University, for his kind help in performing
histopathological results.
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