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Research Article
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Antioxidant Effect of Curcumin Extracts in Induced Diabetic Wister Rats |
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H.K. Hussein
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O.A. Abu-Zinadah
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ABSTRACT
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This study aimed to determine the protective effect of curcumin on streptozotocin (STZ)-induced oxidative stress in various tissues of albino Wister rats. Adult male rats (8 weeks), weighing 195 to 225 g was made diabetic by injecting STZ (65 mg kg-1 body weight) intraperitoneally. During the whole experimental period, animals were fed with a balanced commercial chow and water ad libitum. Diabetic rats given either water or ethanolic curcumin extracts (80 mg kg-1 body weight) in aqueous suspension daily for a period of seven weeks. The levels of oxidative stress parameters and activity of antioxidant enzymes were determined in various tissues. STZ-induced hyperglycemia resulted in increased glucose level, glycosylated haemoglobin in red blood cells and other tissues and altered antioxidant enzyme activities such as AST and ALT. These elevated blood parameters and enzymatic activities induced by hyperglycemia were significantly restored to near normal by oral administration of curcumin once daily for 7 weeks, as compared to untreated rats. There was a significant elevation in the level of liver and kidney malondialdhyde (MDA), while the activities of antioxidant enzymes superoxide dismutase and catalase (SOD and CAT) were significantly decreased in STZ rats which also restored to normal after curcumin treatment. The results obtained indicated that ethanolic extract has more potent protective action than water extract against all hyperglycemic parameters. Biochemical observations were supplemented by histopathological examination of liver and kidney sections. Interestingly, feeding curcumin to the diabetic rats controlled oxidative stress by inhibiting the increase in TBARS and protein carbonyls and reversing altered antioxidant enzyme activities without altering the hyperglycemic state in most of the tissues. So, curcumin appear to be beneficial in preventing diabetes-induced oxidative stress in rats despite unaltered hyperglycemic status.
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Received: March 31, 2010;
Accepted: May 06, 2010;
Published: June 10, 2010
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INTRODUCTION
Hyperglycemia causes the autoxidation of glucose, glycation of proteins and
the activation of polyol metabolism. These changes accelerate generation of
Reactive Oxygen Species (ROS) and increases in oxidative chemical modification
of lipids, DNA and proteins in various tissues. Oxidative stress may play an
important role in the development of complications in diabetes such as lens
cataracts, nephropathy and neuropathy. Glycation reactions, especially Millard
reactions, occur in vivo as well as in vitro and are associated with the chronic
complications of diabetes mellitus and aging and age-related diseases by increases
in oxidative chemical modification of lipids, DNA and proteins (Meghana
et al., 2007). Diabetes mellitus (type 2) is associated with increased
oxidative stress (Mc-Coll et al., 1997). Free
radicals are continually produced in the body as the result of normal metabolic
processes and interaction with environmental stimuli. Under physiological conditions,
a wide range of antioxidant defenses protects against adverse effects of free
radical production in vivo (Halliwell and Gutteridge,
1989). Oxidative stress results from an imbalance between radical production
and reduced activity of antioxidant defenses or both these phenomena. Hyperglycemia
causes release of tissue damaging Reactive Oxygen Species (ROS) balance between
radical production and protective antioxidant defense (Signorini
et al., 2002; Halliwell and Gudtteridge, 1990).
It has been proposed that streptozotocin (STZ) acts as a diabetogenic agent
owing to its ability to destroy pancreatic β-cells, possibly by a free
radical mechanism (Halliwell and Gutteridge, 1994).
The level of lipid peroxidation in cell is controlled by various cellular defense
mechanisms consisting of enzymatic and nonenzymatic scavenger systems, the levels
of which are altered in diabetes (Wohaieb and Godin, 1987).
Moreover, disturbances of antioxidant defense systems in diabetes were shown:
alteration in antioxidant enzyme (Strain, 1991), impaired
glutathione metabolism (McLennan et al., 1991;
Sajithlal et al., 1998) and decreased ascorbic
acid (Jennings et al., 1987).
In recent years, considerable focus has been given to an intensive search for
novel type of antioxidants from numerous plant materials (Srivastava
et al., 1993). Management of diabetes without any side effects is
still a challenge to the medical system. There is an increasing demand by patients
to use the natural product switch antidiabetic activity, because insulin and
oral hypoglycemic drugs possess undesirable side effects (Rao
and Appa, 2001). Plants with antidiabetic activities provide useful sources
for the development of drugs in the treatment of diabetes mellitus. Phytochemicals
isolated from plant source are used for the prevention and treatment of cancer,
heart disease, diabetes and high blood pressure etc. (Waltner-Law,
2002).
Curcumin (diferuloylmethane) is a naturally occurring yellow pigment isolated
from the rhizomes of the plant Curcuma longa (Linn) found in south Asia
(Lodha and Baggha, 2000) and is a potent antioxidant
agent and free radical scavenger (Fujisawa et al.,
2004). Along with being an inhibitor of lipid peroxidation (Sreejayan-
Rao, 1994), it is also an inhibitor of Nitric Oxide Synthase (NOS) overexpression
(Spinas, 1999; Pan et al.,
2000) and of nuclear factor kappa B activation (Weber
et al., 2006). The efficacy of curcumin has been widely observed
in reducing various diabetic secondary complications such as diabetic nephropathy/renal
lesions (Sharma et al., 2006), retinopathy (Kowluru
and Kanwar, 2007), wound healing (Panchatcharam et
al., 2006) and reduction of advanced glycation end products (Sajithlal
et al., 1998). Its potential as a hypoglycemic agent has also been
studied in animals (Pari and Murugan, 2005; Hussain,
2002) and humans (Meghana et al., 2007) with
conflicting results. Furthermore, although many aspects of curcumin-induced
cytoprotection are studied, its efficacy in protecting against streptozotocin-induced
free radical-mediated damage has not been demonstrated so far. We hypothesized
that curcumin may protect cells against streptozotocin-induced oxidative stress
and resulting tissue damage and organ dysfunction. Logically, curcumin would
impart some protection against oxidative damage to different cells, but it would
be of interest to investigate the mode of curcumin-induced cytoprotection. In
this study, the protective action of curcumin on streptozotocin-induced diabetes
mellitus in rats was studied.
MATERIALS AND METHODS
Animals
Eight week male albino Wister rats weighing (195- 225 g) were used in this
study (Vide No. 291, 2009). The animals were obtained from the animal experimental
unit of King Fahd Medical Research Center, King Abdul Aziz University, Jeddah,
Saudi Arabia. The rats were housed in well-aerated individual cages and maintained
in a temperature-controlled room (27±2°C) and humidity 45-56% with12
h light: 12 h dark cycle for one week before and during the experiments. Animals
were provided with standard commercial chow and water ad libitum. The
care and use of all experimental animals complied with relevant animal welfare
laws. Streptozotocin, all reagents and solvents used in this study were purchased
from Sigma-Aldrich Corp., St Luis. MO, USA but Cinnamon powder was obtained
from the local market at Jeddah, Saudi Arabia. Type 2 diabetes mellitus was
induced in overnight fasted rats by a single intraperitonial injection (i.p.)
of 65 mg kg-1 body weight Streptozotocin STZ (Masiello
et al., 1998). STZ was dissolved in citrate buffer (pH 4.5). Hyperglycemia
was confirmed by the elevated glucose levels in plasma, determined at 72 h and
then on day 7 after injection. The animals with blood glucose concentration
more than 200 mg dL-1 will be used for the study.
Preparation of Curcumin Extract
The dried powder was defatted with petroleum ether (100 g in 200 mL ether).
The defatted material was extracted with 95% ethanol and then vacuum dried.
One part of powder was extracted in boiling water and then filtered and vacuum
dried.
Experimental Design
In the experiment, a total of 40 rats (30 diabetic surviving rats, 10 normal
rats) were used. The rats were divided into four groups of 10 each. The experimental
period was seven weeks beginning after the induction of STZ diabetes. Group
I: normal untreated rats. Group II: diabetic control rats (STZ group). Group
III and IV: were diabetic rats given either aqueous or ethanolic extracts of
curcumin (80 mg kg-1 body weight) in aqueous suspension daily using
an intragastric tube (Arun and Nalini, 2002) for seven
weeks. At the end of experimental period, the rats were deprived of food overnight
and blood was collected in a tube containing potassium oxalate and sodium fluoride
for the estimation of blood glucose, haemoglobin and glycosylated haemoglobin.
Plasma was separated for the assay of insulin. The liver and kidney were also
dissected out and were divided into two parts. The first was kept at -20°C
in ice-cold containers for biochemical analysis, while the second part was used
for histopathological studies.
Serum Biochemical Assay
Serum enzymes aspartate aminotransferase (AST) and serum glutamate pyruvate
transaminase (ALT) were determined according to Reitman
and Frankel (1957).
Estimation of MDA, SOD, CAT in Liver and Kidney Tissues
Liver and kidney samples were dissected out and washed immediately with
ice cold saline to remove as much blood as possible. Each tested tissue homogenates
(5% w/v) were prepared in cold 50 mM potassium phosphate buffer (pH 7.4) using
glass homogenizer in ice. The cell debris was removed by centrifugation at 5000
rpm for 15 min at 40°C using refrigerated centrifuge. The supernatant was
used for the estimation of malondialdehyde (MDA) (Ohkawa
et al., 1979), superoxide dismutase (SOD) (Kakkar
et al., 1972) and catalase (CAT) (Sinha, 1972)
levels.
Histopathological Studies
The liver and kidney tissues was dissected out and fixed in 10% formalin,
dehydrated in gradual ethanol (50-99%), cleared in xylene and embedded in paraffin.
Sections were prepared and then stained with hematoxylin and eosin dye for microscopic
investigation.
Statistical Analysis
Statistical analysis was performed on a PC using SPSS, V.13, (special package
for social sciences). Data are presented as arithmetic mean±SD. The difference
among means has been analyzed by one way ANOVA followed by student t-test. A
value of p<0.05 was considered as statistically significant.
RESULTS AND DISCUSSION The results of protective effect of water or ethanol extracts of curcumin on streptozotocin-induced diabetic rats (STZ) are shown in Table 1. In the STZ group, serum AST and ALT were significantly increased as compared to control group (p<0.001). The elevated activities of serum AST and ALT were significantly reduced in the animal groups treated with either water or ethanolic extracts. Treatment with ethanolic extract showed significantly more activity (p<0.001) than with water extract. Thus, the ethanol extract treated group was superior to the water extract. Results obtained revealed an increase in the level of liver and kidney MDA in STZ rats compared to control group. Treatment with extracts significantly prevented this raise in levels. The activities of SOD and CAT were significantly reduced in the STZ group, while they were significantly elevated near the normal values in the groups pretreated with either extracts. Ethanolic extract has been shown to be more protective than water extract. Table 1: |
Antioxidant enzyme activities of liver and kidney of rat;
superoxide dismutase (SOD), catalase (CAT), lipid peroxide 7 product or
Malendialdlyde (MDA) and serum aminotransferase enzymes (ALT and AST) of
all studied groups (Mean±SD) |
 |
STZ: Streptozotocin, WE: Water extract, EE: Ethanol extract,
P1: Comparison to normal control, P2: Comparison to STZ group, P3: Water
E versus ethanol E, N.S= Not significant |
| Fig. 1: |
Effect of curcumin on (a) The levels of blood glucose, (b)
Plasma insulin, (c) Total haemoglobin and (d): Glycosylated haemoglobin
in normal and experimental rats: STZ, Diabetic control; STZ+EE, Diabetic
treated with ethanolic curcumin extract; STZ+WE, Diabetic treated with water
curcumin extract. Values are given as means for 10 rats in each group±SD |
The levels of blood glucose, total haemoglobin, glycosylated haemoglobin and
plasma insulin of different experimental groups were shown in Fig.
1a-d. There was a significant elevation in blood glucose
level, whereas plasma insulin levels decreased significantly in diabetic rats
(STZ groups), compared with normal rats. Administration of water or ethanolic
curcumin extracts tended to bring blood glucose and plasma insulin towards normal.
The diabetic control rats showed a significant decrease in the level of total
haemoglobin and significant increase in the level of glycosylated haemoglobin.
No significant difference between liver and kidney parameters were found in
all studied groups. Oral administration of water and ethanolic curcumin extracts
to diabetic rats significantly restored total haemoglobin and glycosylated haemoglobin
levels. The effect of ethanolic extract was more prominent when compared with
water extract.
Figure 2 shows the histological examination of liver sections
of control animals (Fig. 2A) showed normal hepatic cells with
well preserved cytoplasm prominent nucleus. The livers of STZ rats showed massive
fatty changes, necrosis and broad infiltration of the lymphocytes (Fig.
2B). The histological architecture of liver sections of the rats treated
with either aqueous (Fig. 2C) or ethanolic extracts (Fig.
2D) showed more or less normal patterns, with a mild degree of fatty change,
necrosis and lymphocyte infiltration, almost comparable to those of the control
group.
| Fig. 2: |
(A) Normal hepatic tissues showing hepatic strands of cells
around the central vein (CV) leaving blood sinusoids (S) X 440, (B) hepatic
tissues of STZ group showing cellular necrosis around the central veins
(arrow) X 250, (C) hepatic tissues pretreated with water extract X 440 and
(D) pretreated with ethanol extract showing absence of necrosis X 750 (H
and E stains) |
Pathological changes of kidney (Fig. 3) showing that the
normal renal tissues illustrated in Fig. 3A which showing
normal uriniferous tubules and glomeruli were changed in diabetic control rats
(STZ group). Diabetic control rat's kidney showed tubular epithelial damage,
capillary proliferation certain degenerated uriniferous tubules and dilatation
of Bowman's capsule (Fig. 3B). The above pathological changes
were reduced in rats treated with water and ethanolic curcumin extracts (Fig.
3C and D, respectively).
Although many reports confirm the efficacy of curcumin in cytoprotection of
various cell lines against toxicity (Grandjean-Laquerriere
et al., 2002; Yadav et al., 2005;
Masamune et al., 2006) few studies report the
efficacy of curcumin in mitigating streptozotocin-induced damage to liver and
kidney. Most diabetes related studies using curcumin show the efficacy of oral
administration at various doses for reduction of secondary complications in
streptozotocin-induced diabetic animals (Babu and Srinivasan,
1995; Nishizono et al., 2000; Srinivasan
et al., 2003). However, almost no reports exist that show the prophylactic
importance of curcumin as a diabetic protective agent. Present findings here
come in agreement with the above cited findings and contribute towards retention
of type 2 diabetes which is the most prevalent and serious metabolic disease
affecting people all over the world and cause secondary complications by scavenging
free radicals that cause pathological changes and dysfunction of various organs.
| Fig. 3: |
(A) Normal renal tissues showing normal urineferous tubules
(u) and glomeruli (G) X40, (B) renal tissues of STZ group showing certain
degeneratedated urineferous tubules (D) and dilatation of Bowman's capsule
(DT), X 440, (C): renal tissues pretreated with water extract X 440 and
(D) Pretreated with ethanol extract showing normal renal structure X 750
(H and E stains) |
Present results support the finding of Koenig et al.
(1976), who stated that the glycosylated haemoglobin was significantly increased
in diabetic control rats and this increase is directly proportional to fasting
blood glucose. Anemia is much more common disease in type 2 diabetic patients,
contributing to the pathogenesis of diabetic complications. In the present study,
the decreased concentration of haemoglobin indicates the anemia in STZ diabetic
rats, in as much as during diabetes, the excess glucose transport in the blood
reacts with haemoglobin to form glycosylated haemoglobin. Free radicals react
with lipids and causes peroxidative changes that result in enhanced lipid peroxidation
(Simmons, 1984; Girotti, 1985).
In this study, the lipid peroxidation markers (TBARS) were elevated in erythrocytes
of diabetic rats which support the results reported earlier by Zhang
and Swaan (1999). The increase in lipid peroxidation might be a reflection
of decrease in enzymatic and nonenzymatic antioxidants of defense systems.
Serum AST and ALT activities were used as a marker of tissue damage. Diabetes
mellitus by STZ produces an experimental damage due to its toxic metabolite
(Zhang and Swaan, 1999). The toxic metabolite free radical
is produced by cytochrome p450 which further reacts with oxygen to produce trichloromethyl
peroxy radicals. These radicals bind covalently with the macromolecule and cause
peroxidative degradation of lipid membranes of the liver and kidney. The reduction
of AST and ALT activities by the extracts is an indication of repair of tissue
damage induced by diabetes complications. This is in agreement with Shahidi
and Wanasundara (1992), who found that serum transaminases returned to normal
activities with the healing of tissue parenchyma and regeneration of hepatocytes
and renal tissues. The ethanolic extract induced suppression of increased ALT
and AST activities. Thus, administration of ethanolic or aqueous extracts of
curcumin revealed protective activity against the toxic metabolites of diabetes,
which is also supported by histological studies.
Treatment with curcumin brought back lipid peroxidation markers to near normal
levels, which could be as a result of improved glycemic control and antioxidants
status. We have reported that curcumin has significant glucose reducing property
in STZ diabetic rats. Increased lipid peroxidation under diabetic conditions
can be due to increased oxidative stress in the cell as a result of depletion
of antioxidant scavenger systems. Associated with the changes in lipid peroxidation
the diabetic tissues showed decreased activities of key antioxidants SOD and
CAT and increase MDA which play an important role in scavenging the toxic intermediate
of incomplete oxidation. SOD and CAT are the two major scavenging enzymes that
remove toxic free radicals in vivo. Previous studies have reported that
the activity of SOD is low in diabetes mellitus (Feillet-Coudray
et al., 1999) come in agreement with our results. A decrease in the
activity of these antioxidants can lead to an excess availability of superoxide
anion O2←- (free radical anion) and hydrogen peroxide in biological
systems, which intern generate hydroxyl radicals, resulting in initiation and
propagation of lipid peroxidation (Kumthekar and Katyare,
1992). The result of increased activities of SOD and CAT suggest that curcumin
contains a free radical scavenging activity, which could exert a beneficial
effect against pathological alterations caused by the presence of O2←
and OH←. The increased activity of SOD accelerates dismutaion of O2←-
to hydrogen peroxide (H2O2) which is removed by CAT (Aebi,
1984). This action could involve mechanisms related to scavenging activity
of curcumin. Lipid peroxidation is accelerated when free radicals are formed
as the results of losing a hydrogen atom from the double bond in the structure
of unsaturated fatty acids. The free radical scavenging activity of water or
ethanolic extracts of curcumin was evaluated.
Scavenging of free radicals is one of the major antioxidation mechanisms to
inhibit the chain reaction of lipid peroxidation. Reduced lipid peroxidation
was revealed by a significant decrease in MDA level in groups pretreated with
water or ethanol extracts, simultaneously with a significant elevation in SOD
and CAT activities. The present study revealed that SOD and CAT activities decreased
in STZ animals, which may be due to altered antioxidant status. This is in accordance
with results that indicated a decreased CAT in STZ animals may be due to the
utilization of antioxidant enzymes in the removal of released H2O2
released (Cerutti et al., 1994). SOD and CAT
activities increased significantly in the treated group versus the untreated
animals.
In present study, histopathological observation in diabetic control rats causes
conges mild inflammation; sinusoidal congestion with fatty degeneration in the
form of fat lake in the liver and tubular epithelial damage messangial capillary
proliferation; fatty infiltration in the kidney. The reaction is provoked by
the increased production of highly reactive intermediates of STZ, which are
normally detoxified by endogenous Growth Stimulating Hormone (GSH) but when
present in excess, can deplete GSH stores, allowing the reactive intermediate
to react with and destroy hepatic, renal cells (Blum and
Fridovich, 1985). The above pathological changes were reduced in diabetic
rats treated curcumin. The histological evidence of diabetic control rats suggest
that structural alterations at the end of experiment are due to STZ induced
free radical generation quite early in diabetes. Thus in addition to blood glucose
lowering effect, histopathological observations also supports the notion that
curcumin produced significant antihyperglycemic activity by protecting the tissues
against STZ action. The results obtained revealed that ethanolic extract of
curcumin has more potent antioxidant activity than water extract. The antioxidant
properties of curcumin extracts are attributable to the ability of its phenolic
constituents to quench reactive oxygen species. The protective effect is documented
by the biochemical and histopathological data obtained. This data supports the
uses of curcumin extract in treatment of some hepatic and renal disorders.
In conclusion, the present investigation shows that curcumin possesses antioxidant effect that may contribute to its protective action against lipid peroxidation and enhancing effect on cellular antioxidant defense. This activity contributes to the protection against oxidative damage in STZ induced diabetes. Further study will be carried out to identify the types of phenolic compounds present and to test for antitumor activity.
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