Experimental and Toxicologic Pathology 64 (2012) 487–493

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Experimental and Toxicologic Pathology

journal homepage: www.elsevier.de/etp

Protective effect of curcumin on cypermethrin-induced oxidative

stress in Wistar rats
Palanisamy Sankar, Avinash G. Telang ∗ , Ayyasamy Manimaran
Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar 243122, Bareilly, Uttar Pradesh, India

a r t i c l e i n f o a b s t r a c t

Article history: The aim of present study was to investigate the protective effect of curcumin on cypermethrin-induced
Received 8 July 2010 changes in blood biochemical markers and tissue antioxidant enzyme in rats. Rats were divided into
Accepted 1 November 2010 six groups of six each: group I used as control and II and III groups were used as vehicle control. While,
groups IV, V and VI were orally treated with curcumin (100 mg/kg body weight), cypermethrin (25 mg/kg
Keywords: body weight) and cypermethrin plus curcumin, respectively for 28 days. Serum biochemical markers
Cypermethrin
were measured in the serum, and the levels of lipid peroxidation and antioxidant enzyme activity were
Curcumin
determined in the liver, kidney and brain. Cypermethrin administration caused elevated level of blood
Oxidative stress
Antioxidants
biochemical markers in serum and lipid peroxidation in liver, kidney and brain. While the activities
Rats of non-enzymatic and enzymatic antioxidants levels were decreased except superoxide dismutase in
liver, kidney and brain tissues. The presence of curcumin with cypermethrin significantly decreased the
blood biochemical markers and lipid peroxidation but significantly increased the reduced glutathione,
catalase and glutathione peroxidase level and preserved the normal histological architecture of the liver,
kidney and brain. Our results indicate that curcumin can be potent protective agent against cypermethrin-
induced biochemical alterations and oxidative damage in rats.
© 2010 Elsevier GmbH. All rights reserved.

1. Introduction on pesticides show that their toxicity is linked to different mech-

anisms, including reactive oxygen species (ROS) generation and
At present, synthetic pyrethroids are highly active insecticides oxidative stress (Gupta et al., 1999). CYP and other pyrethroids
which account for 30% of insecticides used globally (Prasanth and are metabolized in the liver via hydrolytic ester cleavage and
Rajini, 2005). There are serious concerns on the potential risks of oxidative pathways by the CYP-450 enzymes yield ROS, which
exposure to pyrethroid insecticides with increasing production and may be responsible for oxidative stress in mammals (Floodstrom
application (Adelsbach and Tjeerdema, 2003). Cypermethrin (CYP) et al., 1988; Klimek, 1990). The ROS directly react with cellular
is a member of the family of synthetic pyrethroids, belongs to type biomolecules; damage lipids, proteins and DNA in cells and that can
II class pyrethroids and is widely used in agricultural and other ultimately lead to cell death. Pyrethroids are rapidly metabolized in
domestic applications. Accidental exposure with pyrethroids in mammals, and several studies have shown that CYP damages the
human and animals result from advertent use. Populations at high- brain, liver, kidney, and erythrocytes by causing oxidative stress
est risk of high dose exposure are producers, hygienic and pesticide (Zegura et al., 2004; Giray et al., 2001; Kale et al., 1999).
workers, and small farm owners applying CYP for plant protection; During the past few years, estimation of free radical gener-
low dose exposure originates mainly from the household appli- ation and antioxidant defense has become an important aspect
cation of insecticides, contaminated food and water (Gorell et al., of investigation in mammals (Zini et al., 1993). A positive cor-
1998). CYP can be found in trace amounts or at higher concentra- relation has been established between dietary supplementation
tions in soil and air. In mammals, CYP can accumulate in body fat, with certain vegetables and plant products and the reduction of
skin, liver, kidneys, adrenal glands, ovaries, lung, blood, and heart toxic effects of various toxicants and environmental contaminants
(Hall et al., 1980; Manna et al., 2004). CYP is highly hydrophobic (Nandi et al., 1997). Plant products are known to exert their protec-
compounds and this suggests that their action in biological mem- tive effects by scavenging free radicals and modulating antioxidant
branes might be related to association with integral proteins and defense system. Curcumin (CMN) (diferuloylmethane), a yellow
with phospholipids (Michelangeli et al., 1990). Previous studies orange dye derived from the rhizomes of Curcuma longa turmeric,
is used as a spice and food-coloring agent in cooking (Joe et al.,
2004: Maheshwari et al., 2006). Curcumin represents a class of anti-
∗ Corresponding author. Tel.: +91 581 2300291; fax: +91 581 2300361. inflammatory and antioxidants reported to be a potent inhibitor of
E-mail address: [email protected] (A.G. Telang). ROS formation (Venkatesan et al., 2000; Biswas et al., 2005). Reddy

0940-2993/$ – see front matter © 2010 Elsevier GmbH. All rights reserved.
doi:10.1016/j.etp.2010.11.003
488 P. Sankar et al. / Experimental and Toxicologic Pathology 64 (2012) 487–493

and Lokesh (1994) indicated that CMN is a potent scavenger of a 2.5. Serum biochemical estimations
variety of ROS including superoxide anion radicals and hydroxyl
radicals. CMN administration has been reported to prevent the The activity of alanine amino transferase (ALT), aspartate amino
arsenic, gentamicin and acetaminophen-induced oxidative stress transferase (AST) and level of blood urea nitrogen (BUN) and cre-
in rats (Fatma et al., 2009; Farombi and Ekor, 2006; Cekmen et al., atinine estimations were carried out using commercially available
2009a,b). CMN also prevent the free radical formation in myocardial kits (Span Diagnostics Ltd; India).
ischemia in rats (Manikandan et al., 2004) and paraquat induced
lung injury (Venkatesan, 2000). Based on the above considerations,
2.6. Assessment of oxidative stress and antioxidant enzyme
the goal of the present study was to determine the possibilities of
activity
CMM in preventing or minimizing the serum biochemical alter-
ations and oxidative stress induced by subacute administration of
Estimations of different oxidative stress-related biochemical
CYP in rats.
parameters in liver, kidney and brain were carried out. A 200 mg
of sample was taken in 2 ml of ice-cold phosphate buffer saline.
Another 200 mg of sample was separately taken in 2 ml of 0.02 M
2. Materials and methods
EDTA for reduced glutathione (GSH) estimation. The homogenate
(10%) prepared with homogenizer (IKA, Germany) under ice-cold
2.1. Experimental animals
condition was centrifuged for 10 min at 3000 rpm and the super-
natant was stored at −20 ◦ C until assay.
The study was conducted in adult male Wistar rats (6–8 weeks,
Lipid peroxidation (LPO) was evaluated in terms of malondi-
100–120 g) procured from the Laboratory Animals Resources Sec-
aldehyde (MDA) production (Shafiq-u-Rehman et al., 1984). GSH
tion of the Institute. Animals were maintained under standard
content was evaluated by the method of Sedlak and Lindsay (1968).
management conditions and handled as per the Institute Ani-
Catalase (CAT) activity was assayed by the method as described
mal Ethics Guidelines. Rats were given standard rat feed and
by Aebi (1983). The activity of superoxide dismutase (SOD) was
water ad libitum throughout the experiment. All the animals were
measured as per the method of Madesh and Balasubramanian
quarantined for a period of at least 7 days before beginning of
(1998). Glutathione peroxidase (GPx) activity was determined by
the experiment. The animals were handled and the study was
the method of Paglia and Valentine (1967). The protein content was
conducted in accordance with the Institute guide lines for the pro-
estimated by the method of Lowry et al. (1951) using bovine serum
tection of animal welfare.
albumin as standard.

2.2. Chemicals 2.7. Histopathology

Cypermethrin (CYP; 96%) was a kind gift from Gharda chemi- Representative pieces of liver, kidney and brain were collected
cals, Mumbai. CMN was purchased from M/s Sigma Chemicals, USA. and fixed in 10% neutral buffered-formalin. After proper fixation
All other chemicals used were of analytical grade from E. Merck, (48 h), tissues were cut into thinner pieces (2–3 mm thick). These
Germany and India; Sigma Chemicals, USA and SRL Chemicals, samples were embedded in paraffin blocks. Sections of about 5 ␮m
India. were cut, stained with hematoxylin and eosin by the standard
method, and examined under light microscope (Luna, 1968).

2.3. Dose selection

2.8. Statistical analysis
CYP was dissolved in ground nut oil and administered orally for
Data have been expressed as mean ± SEM. The change in CYP
28 days, at a dose rate of 25 mg/kg body weight/day (1/10 of LD50;
mediated effects was compared to the control values, while CYP
Cantalamessa, 1993) by oral gavage. CMN was dissolved in 1% gum
plus CMN mediated alterations was compared with the CYP group.
acacia and given orally for 28 days, at a dose rate of 100 mg/kg body
Statistical analysis of data was performed using GraphPad InStat.
weight/day. CMN was administered 1 h prior to CYP treatment.
Data were analyzed by ANOVA and means were compared with
Tukey multiple comparison test. A value of p < 0.05 was considered
statistically significant.
2.4. Experimental design

Rats were divided into 6 groups of 6 animals each. Control rats 3. Results
were given water (group I), while groups 2 and 3 were given once
equivalent amount of ground nut oil and gum acacia (1%; vehi- 3.1. Body weight
cle control), respectively. Rats of group 4 were administered CYP
(25 mg/kg, orally) daily for 28 days. Group 5 was administered CMN Clinical signs of toxicity such as slight nervousness, mild depres-
(100 mg/kg, orally) daily for 28 days. Group 6 was administered CYP sion and abnormal gait were observed in cypermethrin-exposed
(25 mg/kg, orally) and CMN (100 mg/kg, orally) daily for 28 days. rats. The animals of other groups including those treated with CYP
Body weights of rats were recorded initially and at the end of the plus CMN did not exhibit any apparent signs of toxicity. There was
experiment. All the animals were observed daily for the presence of no mortality in rats with any of the treatments. At term, CYP caused
clinical signs of toxicity during the entire period of the study. Rats significant reduction in body weights of animals treated with CYP
were sacrificed at the end of the exposure period. Blood was col- alone as compared to control group (Table 1). The presence of
lected by heart puncture from each rat in a dry, clean and sterilized CMN with CYP significantly increased the body weight as com-
test tube, and allowed to clot. The sera samples were preserved at pared to CYP alone treated rats. There were no differences in any of
−20 ◦ C until the analysis was performed. Liver, kidney and brain parameters between the water and vehicle control group (results
were excised, washed with ice cold normal saline and used for are not shown); therefore, all comparisons are made to the water
histopathological examination and oxidative stress assay. control.
 P. Sankar et al. / Experimental and Toxicologic Pathology 64 (2012) 487–493 489

Table 1
Effect on body weight (g) following 28-days exposure with cypermethrin and cyper-
methrin plus curcumin.

Group Dose Body weight (g)

0 day 28 days

Control – 125.83 ± 2.39 227.50 ± 4.23

CMN 100 mg/kg 126.67 ± 3.07 223.50 ± 4.43
CYP 25 mg/kg 127.13 ± 1.54 199.16 ± 3.00a
CYP + CMN 25 + 100 mg/kg 125.00 ± 1.83 213.67 ± 2.11b

Values are represents mean ± SEM of 6 rats. Significant differences are indicated by
superscript a: compared to control (p < 0.05), superscript b: compared to CYP group
(p < 0.05). C: control, CMN: curcumin, CYP: cypermethrin.

3.2. Effects on serum biochemical markers

AST and ALT are indicators of hepatic function. Compared to the Fig. 2. Effects of 28 days oral administration of CYP, CMN and CYP plus CMN on
lipid peroxidation level of liver, kidney and brain in male rats. Each bar represents
control group, the CYP treated group had significantly elevated AST
mean ± SEM of 6 rats. Significant differences are indicated by superscript a: com-
and ALT in serum (Fig. 1A and B). The levels of BUN and creatinine pared to control, superscript b: compared to CYP group. C: control, CMN: curcumin,
were significantly elevated by the CYP exposure in serum (Fig. 1C CYP: cypermethrin, CMN at 100 mg/kg and CYP at 25 mg/kg.
and D). When the CYP plus CMN-treated group was compared to
the CYP-treated group, they had significantly lower AST, ALT, and presence of CMN with CYP caused reduction in the elevated tissue
BUN levels. LPO in liver, kidney and brain tissues.

3.3. Effects on LPO 3.4. Effects on GSH content

Fig. 2 depicts the results of LPO in liver, kidney and brain. LPO Effects on the GSH in liver, kidney and brain are presented in
was measured as MDA concentration. Significant enhancement was Fig. 3. CYP treatment significantly decreased reduced glutathione
observed in LPO in the tissues examined after CYP exposure. The level in liver, kidney and brain tissues. Simultaneous treatment

Fig. 1. Effects of 28 days oral administration of CYP, CMN and CYP plus CMN on (A) aspartate aminotransferase, (B) alanine aminotransferase, (C) blood urea nitrogen and (D)
creatinine activities in serum of male rats. Each bar represents mean ± SEM of 6 rats. Significant differences are indicated by superscript a: compared to control, superscript
b: compared to CYP group. C: control, CMN: curcumin, CYP: cypermethrin, CMN at 100 mg/kg and CYP at 25 mg/kg.
490 P. Sankar et al. / Experimental and Toxicologic Pathology 64 (2012) 487–493

Fig. 3. Effects of 28 days oral administration of CYP, CMN and CYP plus CMN
on reduced glutathione of liver, kidney and brain in male rats. Each bar repre-
sents mean ± SEM of 6 rats. Significant differences are indicated by superscript a:
compared to control, superscript b: compared to CYP group. C: control, GN CMN:
curcumin, CYP: cypermethrin, CMN at 100 mg/kg and CYP at 25 mg/kg. Fig. 5. Effects of 28 days oral administration of CYP, CMN and CYP plus CMN on
super oxide dismutase of liver, kidney and brain in male rats. Each bar represents
mean ± SEM of 6 rats. Significant differences are indicated by superscript a: com-
with CYP and CMN showed significant increase in reduced glu- pared to control, superscript b: compared to CYP group. C: control, CMN: curcumin,
tathione level in all the tissues, when compared to animal treated CYP: cypermethrin, CMN at 100 mg/kg and CYP at 25 mg/kg.
with CYP alone.
blood vessels in meninges (Fig. 7C) with increase in the perivascular
3.5. Effects on enzymatic antioxidant enzyme space was observed. Many neurons appeared swollen and oth-
ers vacuolated. CMN treatment showed decrease in degenerative
CYP treatment significantly attenuated the CAT activity in liver, changes in liver, decreased the tubular degeneration and reduced
kidney and brain tissues (Fig. 4) and CMN treatment significantly the histological alteration in brain as compared to the CYP alone
restored the enzyme to near normal status in all the tissues. CYP treated groups (Fig. 8A–C).
exposure resulted in significant elevation in superoxide dismutase
activity in liver, kidney and brain (Fig. 5). Simultaneous treatment 4. Discussion
with CYP and CMN showed significant restoration in SOD level in
liver and brain but no effect on kidney tissue. The activity of glu- In the present experiment, significant decrease in body weight
tathione peroxidase was decreased in liver kidney and brain (Fig. 6). at end of the experimental period following administration of CYP
CYP plus CMN significantly restored the activity of glutathione per- in rat has been observed. It may be attributed to the effect of insec-
oxidase, when compared to animals treated with CYP alone. ticide on gastrointestinal tract resulting in decreased appetite and
absorption of nutrients from gut (Venkateshwarlu et al., 1997) or
3.6. Histopathology might be due to direct toxicity of CYP. The increased AST and ALT
activities as observed in the present study could be due to cellular
The administration of CYP for 28 days resulted in enlargement injury of the liver tissues. These observations matched with ear-
of sinusoids space, degeneration in hepatic cords and hepatocytes lier finding of CYP toxicity in rats (Gupta and Bhaumik, 1988) and
in the centrilobular areas with frequent karyomegaly and binu- rabbits (Yousef et al., 2003). The increase in the activities of these
cleations (Fig. 7A) were found in the livers of the rats. After the enzymes in serum is indicative for liver damage and thus causes
exposure of CYP for 28-days, tubular lining cells showed, degen- alteration in liver function. The present study indicated that treat-
erative necrotic changes, swollen and enlarged desquamated cells ment with CYP caused significant increase in serum creatinine and
with cytoplasmic esonophilia (Fig. 7B). In the brain engorgement of BUN. Similar changes in creatinine and urea values were reported in

Fig. 4. Effects of 28 days oral administration of CYP, CMN and CYP plus CMN on catalase level of liver, kidney and brain in male rats. Each bar represents mean ± SEM of 6
rats. Significant differences are indicated by superscript a: compared to control, superscript b: compared to CYP group. C: control, CMN: curcumin, CYP: cypermethrin, CMN
at 100 mg/kg and CYP at 25 mg/kg.
 P. Sankar et al. / Experimental and Toxicologic Pathology 64 (2012) 487–493 491

Fig. 6. Effects of 28 days oral administration of CYP, CMN and CYP plus CMN on glutathione peroxidase of liver, kidney and brain in male rats. Each bar represents mean ± SEM
of 6 rats. Significant differences are indicated by superscript a: compared to control, superscript b: compared to CYP group. C: control, CMN: curcumin, CYP: cypermethrin,
CMN at 100 mg/kg and CYP at 25 mg/kg.

rabbits (Yousef et al., 2003). The elevation of serum creatinine and reduces hydrogen peroxide to molecular oxygen and water. Fur-
BUN enzymes are considered as significant markers of renal dys- thermore, it has been suggested that LPO might be a contributing
function. Elevated blood urea is correlated either with an increased factor for decrease in the catalase activity during cypermethrin tox-
protein catabolism in the mammalian body or from a more effi- icity (Atessahin et al., 2005). Glutathione related enzymes such as
cient conversion of ammonia to urea as a result of increased glutathione peroxidase (GPx) function either directly or indirectly
synthesis of enzyme involved in urea production (Rodwell, 1979). as antioxidants. In our study, there was a significant decrease in
The histopathological observations in CYP-treated rats showed the the activities of glutathione peroxidase in liver, kidney and brain of
enlargement of sinusoidal space, degeneration in hepatic cords and CYP exposed rats. GPx is non-specific for H2 O2 and a lack of sub-
hepatocytes in the centrilobular areas with frequent karyomegaly strate specificity extends a range of substrates from H2 O2 to organic
and binucleations. Similar findings of liver damage during CYP toxi- hydroperoxides (Chance et al., 1979). Therefore, an excess of H2 O2
city have been observed earlier in rats (Yavasoglu et al., 2006). After and lipid peroxides are efficiently scavenged by GPx activity. The
exposure of CYP for 28-days, tubular lining cells showed, degenera- depression of this enzyme activity as observed in the present study
tive necrotic changes, swollen and enlarged desquamated cells with reflects perturbations in normal oxidative mechanisms during CYP
cytoplasmic esonophilia (Manna et al., 2010) and in the brain, cere- toxicity. CYP has been demonstrated to cause a significant decrease
bellar and meningeal blood vessels were engorged with red blood in the activities of glutathione peroxidase in the rats (Nasuti et al.,
cells. This could be due to the accumulation of free radicals as the 2003).
consequence of increased LPO by CYP toxicity. CMN, a phenolic compound, exhibits protective effects against
LPO has been extensively used as a marker of oxidative stress. In oxidative damage and it is considered to be a potent cancer chemo-
the present study, CYP treatment produced a significant increase in preventive agent (Duvoix et al., 2005). Rats that received CMN
the level of MDA in the hepatic, renal and brain tissues. The increase along with CYP showed increase in body weight as compared
in the concentration of MDA is an indicator of CYP-induced LPO to CYP alone treated rats which indicate that CMN has appetite
leading to tissue injury. CYP exposure has been shown to cause inducer and anti-stress effect. This finding is in agreement with
decrease in membrane fluidity, thereby increasing LPO (Gabbianelli observation of increased weight gain of rats following treatment
et al., 2004). Glutathione antioxidant system plays a pivotal role with CMN pretreated with arsenic (Fatma et al., 2009). The result
in cellular defence against reactive free radicals and other oxidant showed that CMN treatment prevents the elevation of serum bio-
species. Hepatic GSH plays a crucial role in both scavenging reactive chemical enzymes and histopathological alteration. Kalpana and
oxygen species and the detoxification of xenobiotics (Haque et al., Menon (2004) suggested that CMN exerts its protective effect by
2003). In addition to being a direct free radical scavenger, GSH is modulating the biochemical marker enzymes, LPO and augment-
known to function as a substrate for glutathione peroxidase and ing antioxidant defense system. In the present study there was a
glutathione-S-transferase. Previous studies have shown that CYP significant decrease in the LPO in CYP plus CMN treated group as
treatment depletes GSH levels (Kale et al., 1999) and suggested LPO compared to CYP alone treated group. Treatment with CMN also
as one of the mechanisms of CYP toxicity in rats accompanied by a resulted in decreased LPO. These results are in agreement with pre-
concomitant decrease in cellular GSH concentration. In our study, vious studies (Shukla et al., 2003; Eybyl et al., 2006; Kalpana and
in CYP treated rats, levels of GSH were significantly decreased in Menon, 2004). A protective effect of CMN has also been reported in
liver, kidney and brain. ex vivo experiments against cadmium and lead induced LPO in rat
SOD and CAT are the two enzymes that help to scavenge super- brain homogenates (Daniel et al., 2004). The simultaneous treat-
oxide ions and hydroxyl ions, respectively. The present study ment with CMN elevated the CYP-induced decrease in the levels of
showed an increase in SOD and decrease in catalase activity in GSH. Elevation in the tissue levels of GSH by CMN as observed in
liver, kidney and brain of CYP exposed rats. This increase could the present study is in agreement with earlier findings (Rukkumani
be a consequence of the high production of superoxide anion fol- et al., 2004; Tirkey et al., 2005). In the present study, levels of
lowing the pyrethroid treatment (Kale et al., 1999; Maiti and Kar, CAT, and GPx enzymes in liver, kidney and brain of CYP plus CMN-
1997). Similarly, increased generation of free radicals in fenvaler- treated animals were significantly increased as compared to the
ate pyrethroid treated mice and an increased activity of SOD have CYP treatment group. It is well known that antioxidant enzymes
been reported (Maiti et al., 1995). CAT is a haemoprotein, which play an important protective role against LPO in tissues (Franesco
492 P. Sankar et al. / Experimental and Toxicologic Pathology 64 (2012) 487–493

Fig. 7. (a) Liver (CYP 25 mg/kg): diffuse and severe degeneration of hepatocytes
with distinct karyomegaly and binucleation. (b) Kidney (CYP 25 mg/kg): degener-
ative necrotic changes, swollen and enlarged desquamated cells with cytoplasmic
esonophilia. (c) Brain (CYP 25 mg/kg): engorgement of blood vessels in meninges
with increase in the perivascular space. Fig. 8. (a) Liver (CYP 25 mg/kg + CMN 100 mg/kg): hepatocytes arranged in normal
cord pattern with mild degeneration. (b) Kidney (CYP 25 mg/kg + CMN 100 mg/kg):
mild degeneration but almost normal appearance of kidney glomeruli and tubules.
et al., 1985). CMN has been shown to restore the activities of SOD, (c) (CYP 25 mg/kg + CMN 100 mg/kg): almost normal appearance of brain meninges
and perivascular space.
CAT and GPx during arsenic, gentamicin, ferric nitrilotriacetate and
nicotine-induced toxicity (Fatma et al., 2009; Farombi and Ekor,
2006; Venkatesan et al., 2000; Kalpana and Menon, 2004). Antioxi-
dant mechanism of CMN may include one or more of the following ␤-diketone moiety, exhibited antioxidant activity by cleavage of
interactions, scavenging or neutralizing free radicals (Soudamini the C–C bond at the active methylene carbon between the two
et al., 1992), interacting with oxidative cascade and preventing its carbonyls (Pan et al., 1999). These antioxidant properties seem
outcome (Unnikrishnan and Rao, 1992). CMN possesses distinct to have a role in inhibiting singlet oxygen generation directly or
structural motifs that are responsible for its antioxidant activity. indirectly.
The presence of electron donating groups like phenolic hydroxyl In conclusion, this study indicates that CMN has the protective
groups and a ␤-diketone structure is responsible for the free rad- effect against CYP-induced biochemical alterations and oxidative
ical scavenging activity and inhibiting LPO (Osawa et al., 1995; damage in the various organs of rats. The mechanism for this pro-
Sreejayan and Rao, 1994; Wright, 2002). In addition, CMN pri- tective effect is due its free radical scavenging activity and increased
mary metabolite, tetrahydro curcumin, a major antioxidant with antioxidant enzymes in rats.
 P. Sankar et al. / Experimental and Toxicologic Pathology 64 (2012) 487–493 493

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