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Neuroprotective effect of ginger on anti-oxidant enzymes in streptozotocin-induceddiabetic rats

Kondeti Ramudu Shanmugam a,b, Korivi Mallikarjuna c, Nishanth Kesireddy d,Kesireddy Sathyavelu Reddy a,⇑a Division of Molecular Biology and Exercise Physiology, Department of Zoology, Sri Venkateswara University, Tirupati, AP 517 502, Indiab Department of Nutrition and Dietetics, Faculty of Allied and Health Sciences, University of Kebangsaan Malaysia, Jalan Raja Muda Aziz, 50300 Kuala Lumpur, Malaysiac Laboratory of Exercise Biochemistry, Taipei Physical Education College, Taipei City, 11153 Taiwan, ROCd Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102-1982, USA

a r t i c l e i n f o

Article history:Received 6 July 2010Accepted 15 December 2010Available online 22 December 2010

Keywords:DiabetesGingerAnti-hyperglycemicAnti-oxidantLipid peroxidation

a b s t r a c t

The aim of the present study was to investigate the effect of ginger on oxidative stress markers in themitochondrial fractions of cerebral cortex (CC), cerebellum (CB), hippocampus (HC) and hypothalamus(HT) of diabetic rats. Diabetes exacerbates neuronal injury induced by hyperglycemia mediated oxidativedamage. A marked decrease in anti-oxidant marker enzymes, superoxide dismutase (SOD), catalase(CAT), glutathione peroxidase (GPx), glutathione reductase (GR), reduced glutathione (GSH) and increasein malondialdehyde (MDA) was observed in the diabetic rats. Decreased activities of anti-oxidantenzymes in diabetic rats were augmented on oral administration of ginger. Moreover, ginger administra-tion depleted the MDA level, which was earlier increased in the diabetic rats. These results suggest thatginger exhibit a neuroprotective effect by accelerating brain anti-oxidant defense mechanisms and downregulating the MDA levels to the normal levels in the diabetic rats. Thus, ginger may be used as therapeu-tic agent in preventing complications in diabetic patients.

� 2010 Elsevier Ltd. All rights reserved.

1. Introduction

Diabetes mellitus is one of the most common metabolic disor-ders with a worldwide prevalence estimated to be between 1%and 5% (Meral et al., 2004). In India, over 20 million peoples are af-fected by diabetes and the number are expected to increase to 57million by 2025 (Arvind et al., 2002). The World Health Organiza-tion (WHO) (1985) has declared India as the country with the larg-est number of diabetic subjects in the world. Diabetes is one of thestress related disorder. Diabetes mellitus has been shown to be astate of increased free radical formation (Feillet-Coudray et al.,1999). The existence of oxidative stress resulting from increasedfree radicals has been postulated in diabetes. Animal, humansstudies and in vitro experiments suggest the role for oxidativestress, via an increased formation of free radicals in the pathophys-iology of many complications of diabetes, such as neurological,

cardiovascular, retinal and renal (Brownlee, 2001). Diabetes mani-fested by experimental animal models exhibit high oxidative stressdue to persistent and chronic hyperglycemia, which thereby de-pletes the activity of antioxidative enzymes and thus promote freeradical generation (Baynes and Thorpe, 1996).

Diabetes is metabolic disorder that is known to producechanges in various organs of the body like heart, liver kidneyand brain. Diabetes affects the central nervous system (CNS)and produce disturbances such as neurobehavioral changes, auto-nomic dysfunctions, altered neuroendocrine functions and neuro-transmitter alterations and thus leading to end organ damage(Nishikawa et al., 2000; Brands et al., 2004). The CNS is highlysusceptible to oxidative stress. Most of the reactive oxygen spe-cies (ROS)-dependent central nervous disorders have been ob-served to be actually triggered by the presence of free radicals.Anti-oxidant therapy has proved to be remarkably beneficial tocombat ROS-induced injury in the CNS.

Plants have been the major source of drug for the treatment ofdiabetes in Indian system of medicine and other ancient systems inthe world. Ginger (Zingiber officinale) is widely consumed as spicefor the flavoring of foods. Ginger is reported to have several bene-ficial pharmacological effects (hypoglycemic, insulinotropic, andhypolipidemic) on health in humans (Huang et al., 2004) and inexperimental animals (Akhani et al., 2004; Kondeti et al., 2011).

0278-6915/$ - see front matter � 2010 Elsevier Ltd. All rights reserved.doi:10.1016/j.fct.2010.12.013

Abbreviations: CC, cerebral cortex; CB, cerebellum; HC, hippocampus; HT,hypothalamus; SOD, superoxide dismutase; CAT, catalase; GPx, glutathione perox-idase; GR, glutathione reductase; GSH, reduced glutathione; MDA, malondialde-hyde; CNS, central nervous system; WHO, World Health Organization; ROS, reactiveoxygen species; STZ, streptozotocin.⇑ Corresponding author. Tel.: +91 877 2249666; fax: +91 877 2261801.

E-mail address: ksreddy2008@hotmail.com (K. Sathyavelu Reddy).

Food and Chemical Toxicology 49 (2011) 893–897

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It has been reported that ginger or its extracts posses some phar-macological activities including antiemesis (Sharma and Gupta,1998), analgesic effect (Young et al., 2005), anti-tumor (Katiyaret al., 1996) and anti-oxidant (Shanmugam et al., 2010). Anti-oxi-dants in ginger include gingerols, shogaols and some phenolic ke-tone derivatives. The anti-inflammatory and anti-oxidantproperties in ginger help relieve various inflammatory disorderslike gout, osteoarthritis, and rheumatoid arthritis. It provides sub-stantial relief in pain caused by inflammation and help decreaseswelling and morning stiffness (Habib et al., 2008). Ginger has beenreported to contain many phytochemicals like phenols, flavanoids,terpenoids and other phytochemicals which are responsible fortheir pharmacological activities. Its dried extract contains mono-terpenes and sesquiterpenes.

However, the effects of ginger have not been studied for its anti-oxidant actions on diabetic brain parts. Thus, the present studyaims to investigate the neuroprotective effect of ginger on oxida-tive damage in the brain parts of streptozotocin-induced diabeticrats.

2. Materials and methods

2.1. Animals

Wistar strain male albino rats aged 6 months, weighing 180 ± 20 g were ob-tained from Indian Institute of Science, Bangalore. The rats were housed in cleanpolypropylene cages having six rats per cage and maintained under temperaturecontrolled room (27 ± 2 �C) with a photoperiod of 12 h light and 12 h dark cycle.The rats were given standard pellets diet (Lipton rat feed, Ltd., Pune) and waterad libitum throughout the experimental period.

The experiments were carried out in accordance with guidelines and protocolapproved by the Institutional Animal Ethics Committee (Regd. No. 438/01/a/CPC-SEA/dt.17.07.2001) in its resolution number 9/IAEC/SVU/2001/dt. 4.03.2002.

2.2. Chemicals

STZ was obtained from Sigma chemicals (USA). All the other chemicals usedwere of analytical grade.

2.2.1. Induction of diabetesThe animals were fasted overnight and diabetes was induced by a single intra-

peritoneal injection of a freshly prepared solution of streptozotocin (STZ) (50 mg/kgbody weight) in 0.1 M cold citrate buffer (pH 4.5). The animals were considered asdiabetic, if their blood glucose values were above 250 mg/dl on the third day afterSTZ injection. Ginger treatment was given to the diabetic rats for 30 days.

2.3. Ginger ethanolic extract preparation

The fresh rhizomes of ginger was locally purchased in Tirupati (AP, India) duringthe period of August, identified and authenticated by botanist, Dr. Madhva Chetty inthe department of Botany, S.V. University. A voucher specimen bearing the number1556 is deposited in the department. Two kilograms of air-dried rhizomes of theherb was milled into fine powder mechanically and extracted in cold percolationwith 95% ethanol for 24 h. The extract was recovered and 95% ethanol was furtheradded to the ginger powder and the extraction was continued. This process was re-peated three times. The three extracts were pooled together, combined, filtered andthe filtrate was concentrated to dryness under reduced pressure in a rotary evapo-rator. The resulting ethanolic extract was air-dried, finally give 80 g of dark brown,gelatinous extract of ginger dried rhizomes. Without any further purification, thecrude ethanolic extract was used for the experiments. Dose equivalent to 200 mgof the crude extract per kg body weight, was calculated and suspended in 2%, v/vTween 80 solution for the experiment (Bhandari et al., 2005).

2.4. Grouping of animals

The rats were divided into five groups, six rats in each group and treated asfollows:

Group 1. Normal control (NC): this group of rats received vehicle solution (2% ofTween 80).

Group 2. Ginger treatment (Gt): six rats received ethanolic extract of gingerwith a dose of 200 mg/kg body weight via oral gavage for 30 days.

Group 3. Diabetic control (STZ 50 mg/kg body weight) (DC): streptozotocin isgiven intraperitonially for the induction of diabetes to this group.

Group 4. Diabetic + ginger treatment (D + Gt): diabetic rats received ginger eth-anolic extract (200 mg/kg) for a period of 30 days.

Group 5. Diabetic + glibenclamide treatment (D + Gli): diabetic rats treatedwith glibenclamide (600 lg/kg body weight orally).

After completion of 30 days treatment the animals were sacrificed by cervicaldislocation and the brain tissues were excised at 4 �C. Different regions of braincerebral cortex (CC), cerebellum (CB), hippocampus (HP) and hypothalamus (HT)were isolated according to specific anatomical marks according to Glowinski andIversen (1966). The tissues were washed with ice-cold saline, immersed in liquidnitrogen and immediately stored at �80 �C for further biochemical analysis.

2.5. Isolation of mitochondria

The isolation of mitochondria was done by using the methods of Kaushal et al.(1999). The brain regions were quickly removed and placed in beakers containingchilled (�4 �C) isolation media. The isolation medium for brain contained 0.25 Msucrose, 10 mM Tris–HCl buffer, pH 7.4, 1 mM EDTA and 250 lg BSA/ml. The tissueswere minced if necessary and washed repeatedly with the isolation medium to re-move adhering blood and 10% (w/v) homogenates were prepared using homoge-nizer. The nuclei and cell debris were sedimented by centrifugation at 650g for10 min and discarded. The supernatant was subjected to a further centrifugationat 7500g for 10 min. The resulting mitochondrial pellet was washed by suspendinggently in the isolation medium and by resedimenting at 7500g for 10 min. Finally,the mitochondria were suspended in the isolation medium.

2.6. Analytical procedures

SOD activity was assayed in the mitochondrial fraction by the method of Misraand Fridovich (1972) at 480 nm for 4 min on a Hitachi U-2000 spectrophotometer.Activity was expressed as the amount of enzyme that inhibits the oxidation of epi-nephrine by 50%, which is equal to 1 U per milligram of protein. CAT activity wasdetermined at room temperature by using the modified version of Aebi (1984)and absorbance of the sample was measured at 240 nm for 1 min in a UV-spectro-photometer. Activity of GPx was determined by the method of Flohe and Gunzler(1984) in the presence of NADPH and absorbance was measured at 340 nm usingcumene hydrogen peroxide. GR enzyme activity was determined according to themethod of Carlberg and Mannervik (1985).

The concentration of reduced GSH was measured as described by Akerboom andSies (1981). The extent of lipid peroxidation was estimated as the concentration ofthiobarbituric acid reactive product MDA by using the method of Ohkawa et al.(1979). All the enzyme activities were expressed per mg protein and the tissue pro-tein was estimated according to the method of Lowry et al. (1951) using bovine ser-um albumin (BSA) as a standard.

The blood glucose levels were measured by using Accucheck glucometer (Roche– Germany).

2.7. Statistical analysis

Analysis of variance (ANOVA) and Duncan’s multiple comparison tests amongdata were carried out using the SPSS (Version 13.5; SPSS Inc., Chicago, IL, USA) andM.S. Office, excel software for the significance of the main effects (factors), and treat-ments along with their interactions. Statistical significance was set at p < 0.05.

3. Results

3.1. Blood glucose and body weight changes

The STZ-induced diabetic rats had shown significant increase ofblood glucose levels in comparison to normal control rats, whichfurther increased during the experimental period. Oral administra-tion of ginger significantly decreases the blood glucose levels incomparison to diabetic group. However, glibenclamide treatmentalso decreased the blood glucose levels in a significant mannerwhen compared to diabetic group. The body weight of diabetic ratswas also lower than the control group. However, ginger and gliben-clamide treatments significantly improved the body weight andbrought down towards near normal level (Table 1).

3.2. Anti-oxidant profile and lipid peroxidation

Fig. 1 represents the activity of oxidative stress marker enzymesin the different experimental groups. There was significant deple-tion in the SOD, CAT and GPx activities in the cerebral cortex,

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cerebellum, hippocampus and hypothalamus of the diabetic ratbrain (p < 0.001). However ginger treatment significantly reversesthe SOD, CAT and GPx back to normal levels (p < 0.01).

Fig. 2 depicts the activity of GR and the levels of reducedGSH, MDA in the cerebral cortex, cerebellum, hippocampus and

hypothalamus of all the experimental groups. The activity of GRand reduced GSH level was decreased in all the regions of brainin diabetic group compared normal control, but it increased tothe level of normal controls in the ginger treated diabetic group(p < 0.01).

The production of thiobarbituric acid reactive substances(TBARS), MDA as an index of lipid peroxidation is also presentedin Fig. 2. The results demonstrate that the lipid peroxidation is in-creased in cerebral cortex, cerebellum, hippocampus and hypothal-amus of diabetic brain as compared to normal control group(p < 0.001). However, ginger treatment decreased the lipid peroxi-dation diabetic group (p < 0.01).

4. Discussion

Diabetes is possibly the world’s fastest growing metabolicdisease, and as knowledge of the heterogeneity of this disorderincreases, so does the need for more appropriate therapies(Bandyopadhyay, 2004). Currently, available drug regimens formanagement of diabetes have certain drawbacks such as vascularcomplications, hepatotoxicity, cardiotoxicity and neuronal toxicity.

Table 1Blood glucose levels and body weight changes in STZ-induced rats followed by gingerand glibenclamide treatment.

Groups Blood glucose (mg/dl) Body weight (g)

0th Day 30th Day 0th Day 30th Day

Group I (NC) 81 ± 1.41 94 ± 2.8 195 ± 9.66 215 ± 14.28Group II (Gt) 83 ± 1.47 88 ± 1.87 200 ± 7.07 90 ± 8.01Group III (DC) 253 ± 3.53⁄ 269 ± 15.6⁄ 187 ± 2.73⁄ 150 ± 6.83Group IV (D + Gt) 259 ± 4.09w 138 ± 5.84 185 ± 6.32 190 ± 4.08w

Group V (D + Gli) 260 ± 1.79w 91 ± 3.71w 190 ± 3.12 205 ± 2.07w

All the values are mean ± SD of six individual observations.Values are significant compared to normal control (⁄p < 0.001) and diabetic control(wp < 0.01).

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Fig. 1. Status of superoxide dismutase (SOD), catalase (CAT) and glutathioneperoxidase (GPx) activities in cerebral cortex (CC), cerebellum (CB), hippocampus(HC) and hypothalamus (HT) of rat brain. The values are significant compared to thefollowing: control (⁄p < 0.001), diabetic (wp < 0.01) (Dunnett’s multiple comparisontest).

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Fig. 2. Alterations in glutathione reductase (GR) activity and reduced glutathione(GSH), MDA levels on STZ induction followed by ginger and glibenclamide. Thevalues are significant compared to the following: control (⁄p < 0.001), diabetic(wp < 0.01) (Dunnett’s multiple comparison test).

K.R. Shanmugam et al. / Food and Chemical Toxicology 49 (2011) 893–897 895

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Management of diabetes with the agents devoid of any side effectsis still a challenge to the medical system. This has led to an increasein the demand for natural products with anti-hyperglycemic activ-ity and fewer side effects. Traditional plant medicines are usedthroughout the world for a range of diabetic conditions. The studyof such medicines might offer a natural key to unlock a diabetolog-ist’s pharmacy for the future (Anjali and Manoj, 1995).

Diabetes is associated with a higher oxidative stress. ROS in-duced damage to the insulin-producing pancreatic beta-cells in-duces diabetes. Anti-oxidant therapy involving the use of herbsand spices has been shown to protect the tissues against such dam-age. It has been shown that under physiological conditions glucosemay undergo auto-oxidation and contribute to ROS formation (Sen,1995). Diabetes induced oxidative damage is responsible for thechanges occurring in the activities of anti-oxidant enzymes leadingto impaired neuronal activity.

Streptozotocin injection resulted in diabetes mellitus, whichmay be due to destruction of beta cells of Islets of Langerhans asproposed by others (Kavalali et al., 2002). Diabetes arises from irre-versible destruction of pancreatic beta cells, causing degranulationand reduction of insulin secretion (Zhang and Tan, 2000). STZ-in-duced diabetes is characterized by a severe loss in body weight(Chen and Ianuzzo, 1982) and may exhibit most of the diabeticcomplications such as, myocardial, cardiovascular, nervous,kidney and urinary bladder dysfunction through oxidative stress(Rajasekaran et al., 2005). After 30 days supplementation of etha-nolic extract of ginger to diabetic rats, resulted significant diminu-tion of fasting blood glucose level in respect to diabetic controlrats, but no significant alteration of fasting blood glucose level tothe control, which further strengthen the antidiabetogenic actionof ginger extract. Many investigators reported that phenols, poly-phenolic compounds and flavonoids of ginger are responsible forhypoglycemic and other pharmacological activities (Jiang et al.,2006). The decrease in body weight in diabetic rats shows thatthe loss or degradation of structural proteins is due to diabetes,and structural proteins are known to contribute to the body weight(Rajkumar and Govindarajulu, 1991). The present study demon-strated that ginger treatment for 30 days shows anti-hyperglyce-mic effect in diabetic rats. When diabetic rats were treated withginger, the weight loss was recovered. Our results are supportingits use as folklore medicine for the treatment of diabetes. Gingertreatment was comparable with glibenclamide treatment astandard hypoglycemic drug (Table 1).

Oxidative stress is the imbalance between production and re-moval of reactive oxygen species. Increased oxidative stress, whichcontributes substantially to the pathogenesis of diabetic complica-tions, is the consequences of either enhanced ROS production orattenuated ROS scavenging capacity. Several reports have shownthe alterations in the anti-oxidant enzymes during diabetic condi-tion (Preet et al., 2005). The antioxidative defense system enzymeslike SOD and CAT showed lower activities in cerebral cortex, cere-bellum, hippocampus and hypothalamus during diabetes and theresults agree well with the earlier published data (El-Missiryet al., 2004; Siddiqui et al., 2005). The decreased activities of SODand CAT may be a response to increased production of hydrogenperoxide and superoxide by the auto-oxidation of excess glucoseand non-enzymatic glycation of proteins (Argano et al., 1997).Pigeolet et al. (1990) have reported the partial inactivation of theseenzyme activities by hydroxyl radicals and hydrogen peroxide.

The decreased activity of SOD and CAT could also be due to theirdecreased protein expression levels in the diabetic condition as re-ported recently by Sindhu et al. (2004). Administration of ginger todiabetic rats increased the activities of SOD and CAT and may helpto control free radical, as ginger offered protection to cells againstoxidative stress by scavenging free radicals (Guo et al., 1997)

generated during diabetic condition (Mahesh et al., 2005). The in-creased activities of anti-oxidant enzymes may act as an addedcompensation mechanism to maintain the cell integrity and pro-tection against free radical damage. This may be due to the pres-ence of many anti-oxidant compounds like gingerols, shogaols,phenolic ketone derivatives, volatile oils, and flavonoids in ginger.These anti-oxidant compounds may modulate the anti-oxidant en-zymes in diabetic rats (Manju and Nalini, 2005; Young et al., 2005)(Fig. 1).

A prominent imbalance between reactive oxygen species pro-duction and endogenous anti-oxidant defense mechanism hasbeen confirmed by reduced activity of GPx and GR in diabetic ratsin the present study (Rastogi et al., 2008). Decreased GPx and GRactivities indicates production of lipid peroxides and elevatedH2O2 production. Treatment with ginger significantly potentiatesabove enzyme activities and the results are in agreement withthe previous reports (Levy et al., 1999). Thus, our findings suggestthat ginger exhibits potent anti-oxidant activity by scavenging freeradicals and restoring the imbalance between oxidants/anti-oxi-dant homeostasis developed during diabetic condition (Figs. 1and 2).

Reduced GSH content was decreased in diabetic rats. Depletionof GSH levels enhances cellular damage caused by oxidative stress.Significant depletion of GSH (p < 0.001) in diabetic rats suggests itsincreased utilization against reactive oxygen species (Rastogi et al.,2008). However with ginger treatment in diabetic rats, the GSHlevel is reversed back to normal levels, this shows that gingersanti-oxidant property. Reports are available on anti-oxidant effectof ginger by decreasing lipid peroxidation, increasing GSH leveland maintaining normal levels of anti-oxidant enzymes (Ahmedet al., 2000; Ajith et al., 2007). A number of investigators havereported that phenols, tannins and terpenoids of ginger possessanti-oxidant activity in various experimental models (Younget al., 2005) (Fig. 2).

The increased lipid peroxidation during diabetes, as found inthe present study may be due to the inefficient anti-oxidant systemprevalent in diabetes. (Siddiqui et al., 2005; Rastogi et al., 2008).The elevated lipid peroxidation is responsible for the formationof lipid hydroperoxides in membrane and would result in damageof the membrane structure and inactivation of membrane boundenzymes. The accumulation of lipid peroxides adds hydrophilicmoieties into the hydrophobic phase and thereby brings aboutchanges in the membrane permeability and cell functions (Pascoeand Redd, 1989). Elevated oxidative stress due to this imbalanceleads to neuronal injury through oxidized proteins and augmentedlevels of lipid peroxidation, as indicated by increased MDA contenton STZ induction in the present study. Ginger and glibenclamidetreatments significantly reduces this enhanced lipid peroxidationand the marked activity is consistent with the previously publishedreports of ginger (Srinivasan and Sambaiah, 1991; Afshari et al.,2007). The anti-oxidant compounds and other pharmacologicalcompounds of ginger may inhibit the production of free radicals,and reduced the products of lipid peroxidation (Fig. 2).

In conclusion, the data from our study suggest that ginger exhi-bit neuroprotective effect against oxidative damage in the diabeticrats. Since, ginger has prevented the brain damage from STZ in-duced oxidative stress. It is now apparent that the future approachto treat diabetes and its associated complications must considereither the use of ginger or combinations of herbal plants havingmulti-pharmacological activities. Ginger may be ideal because theycontain a variety of pharmacological compounds with differentknown pharmacological actions. However, further research isneeded, for the better understanding of the mechanism of actionof ginger by which it modulates anti-oxidant enzymes in diabeticcondition.

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Conflict of Interest

The authors declare that there are no conflicts of interest.

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