Antihyperglycemic, antihyperlipidemic, and antioxidant effects of Chaenomeles sinensis fruit extract in streptozotocin-induced diabetic rats

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The rising incidence of diabetes mellitus (DM) is alarming and becoming a major health problem worldwide, which is mainly associated with hyperglycemia, abnormal lipid, and antioxidant profiles. Herbal medicines are being used by about 80% of the
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  RESEARCH ARTICLE Anti-Hyperglycemic, Anti-Hyperlipidemic and AntioxidantPotential of Alcoholic-Extract of   Sida cordifolia  (Areal Part)in Streptozotocin-Induced-Diabetes in Wistar-Rats Mahrukh Ahmad  • Shahid Prawez  • Mudasir Sultana  • Rajinder Raina  • Nrip Kishore Pankaj  • Pawan Kumar Verma  • Shafiqur Rahman Received: 6 April 2013/Revised: 21 May 2013/Accepted: 3 July 2013/Published online: 14 August 2013   The Author(s) 2013. This article is published with open access at Springerlink.com Abstract  Sida cordifolia  is a shrub found throughout thetropical and sub-tropical plains. All parts of the plant areused as anti-rheumatic, antipyretic, anti-asthmatic, laxa-tive, diuretic, vasorelaxative, hypotensive, central nervoussystem depressant, antioxidant, analgesic and hypoglyce-mic. The present study was aimed to evaluate the hypo-glycemic, anti-hyperlipidemic and antioxidant potential of alcoholic-extract obtained from areal part of   S. cordifolia in streptozotocin-induced-diabetes in wistar-rats. Diabeteswas induced with streptozotocin at the intra-peritoneal doseof 55 mg/kg. Diabetic rats were treated with alcoholicextract of   S. cordifolia  at dosage of 200, 400 mg/kg andglibenclamide (5 mg/kg) after sub-acute administration for28 days. Alcoholic extract of   S. cordifolia  at 400 mg/kgsignificantly improved the body-weight whereas signifi-cantly decreased the blood glucose level in diabetic rats.However at 400 mg/kg, the alcoholic extract of   S. cordi- folia  showed beneficial effect indicating significantdecrease in total cholesterol, triglycerides, low densitylipids, plasma-creatinine, plasma-urea nitrogen and lipid-peroxidation and a significant increase in high densitylipid-level in diabetic rats. Interestingly at 400 mg/kg, asignificant increase in antioxidant enzymes such as catalaseand superoxide-dismutase-activity was seen in the diabeticrats. The dose 200 mg/kg of alcoholic extract of   S. cordi- folia  showed non-significant change in diabetic rats. Theabove therapeutic-potential of alcoholic extract of arealparts of plant may be because of the presence of bioactivecompounds such as glycosides, resins, alkaloids, sterols,saponins and flavonoids. Thus, the findings of the presentstudy indicate that the alcoholic extract of   S. cordifolia  atdosage level of 400 mg/kg produces anti-diabetic effect inthe streptozotocin-induced diabetes in wistar-rats. Keywords  Sida cordifolia    Alcoholic-extract   Anti-diabetic    Streptozotocin    Wistar-rats Introduction Diabetes mellitus (DM) is the most common endocrinedisorder characterized by hyperglycemia resulting fromdefects either in insulin secretion or insulin action or both[1, 2]. Diabetes is the third killer disease of mankind after cancer and cardiovascular diseases because of its highprevalence, morbidity and mortality [3]. The efficiency of defense mechanism of body is altered in diabetes whichresults in ineffective scavenging of free radicals andtherefore results in tissue damage [4]. To control the disease, several conventional-drugs areavailable along with insulin but their prolonged use maylead to other complications like blurred vision, hypogly-cemia and a lingering condition like coma [5, 6]. The anti- diabetic-drugs such as modern oral hypoglycemic agents’like sulphonyl-ureas (tolbutamide, glibenclamide) andinsulin-sensitizer (troglitazone) are associated with variousside effects [6]. To reduce its damaging property it is better to use conventional-drugs along with hypoglycemic-herbs[7]. More than 800 plants possess anti-diabetic activity [8, M. Ahmad    S. Prawez ( & )    M. Sultana    R. Raina   N. K. Pankaj    P. K. VermaDivision of Pharmacology and Toxicology, FVSc&AH,Sher-e-Kashmir University of Agricultural Sciences &Technology of Jammu, RS Pura, Jammu 181102, J&K, Indiae-mail: shahidprawez@gmail.comS. RahmanDivision of Pathology, FVSc&AH, Sher-e-Kashmir Universityof Agricultural Sciences and Technology of Jammu, RS Pura,Jammu 181102, J&K, India  1 3 Proc. Natl. Acad. Sci., India, Sect. B Biol. Sci. (Apr–June 2014) 84(2):397–405DOI 10.1007/s40011-013-0218-2  9].  Sida cordifolia  (Linn.) a shrub belonging to the familyMalvaceae, improves the diabetic conditions [10, 11]. It is found through out the tropical and sub tropical plains of India. Its roots, leaves, stem and seeds are used in the folk medicine as anti-rheumatic [12], antipyretic [13], anti- asthmatic [14], laxative, diuretic [12, 15, 16], vaso-relax- ative [17], hypotensive [14], CNS depressant [18, 19], antioxidant [20] and hypoglycemic effect [21, 22]. Keeping the fact that diabetes is an emerging problem world-wideand is a major concern of developing countries like India;the present study was conducted with the aim to evaluatethe anti-oxidative and anti-diabetic activity of   S. cordifolia in streptozotocin (STZ) induced diabetes in wistar rats. Material and Methods Collection and Extraction of Plant MaterialsThe areal parts of the plant  S. cordifolia  were collected andafter authentication plant material was chopped into smallpieces and kept under shade for drying (30–35   C). Theplant material was pulverized to powder form with mixer-grinder and subjected to alcoholic extraction in soxhlet-apparatus [23] and its % extractability was determined [24]. The presence of phyto-chemicals in the extract suchas alkaloids [25], glycosides [26], saponins [27], sterols [28], resins [29] and flavonoids [30] were determined. Experimental AnimalsThe experimental protocol was duly approved by institu-tional ethics committee. The study was conducted onhealthy wistar rats of either sex weighing 170–230 g,procured from Indian Institute of Integrative Medicine(IIIM Lab), Jammu, India. The animals were providedstandard pelleted ration and  ad libitum  drinking tap water.Prior to the start of the experiment, the rats were accli-matized in the laboratory conditions for a period of morethan 3 weeks. A daily cycle of 12 h of light and 12 h of darkness was provided to animals.Induction of DiabetesStreptozotocin solution (0.5 %) was freshly prepared inice cold sodium citrate buffer (0.1 M; pH 4.5) in avolume of 10 mg/ml and administered to overnight fas-ted wistar-rats intra-peritoneally at the dose of 55 mg kg - 1 body-weight [31–33]. The rats were kept only on glucose solution (5 %) in drinking water for next24 h after the STZ administration to prevent hypogly-cemia [34, 35]. To declare that the rats became diabetic, after 72 h of STZ administration the biomarker of bloodglucose level [36] was determined by using glucometer (Accu-Check, Roche, Germany) and rats showing morethan 200 mg/dl blood glucose level were considered asthe diabetic rats [37]. Experimental DesignA total of 30 healthy-wistar rats were selected and dividedinto five-groups containing six animals in each group.Diabetes was induced in rats of group II, III, IV and Vwhereas group I served as control. The diabetic rats of group II acted as diabetic control only treated with car-boxy-methyl-cellulose (1 %) whereas groups III and IVdiabetic rats were treated with alcoholic extract of   S. cor-difolia  at dosage of 200 and 400 mg/kg after mixing incarboxy-methyl-cellulose (1 %) for 28 days, respectively.Group V diabetic rats received glibenclamide at dosage of 5 mg/kg orally for 28 days. Blood samples of about 2–4 mlwere collected from retro-orbital sinus of wistar-rats underinhalational anesthesia on day 0, 15 and 29 using capillary-tubes and the blood glucose level was measured at the timeof sample collection. The blood samples were centrifugedat 3,000 rpm for 15 min to harvest the plasma which waskept in clean sterile glass test tubes at  - 20   C for furtherbiochemical analysis. The sediment left after taking out theplasma, from which WBC buffy-coat was removed. Theleft-over erythrocyte sediment was then washed 2–3 timesand diluted with gentle pouring of normal saline solution inthe ratio of 1:1 on v/v basis and thoroughly mixed witherythrocyte sediment to make 1 % and 33 % hemolysateused for the estimation of anti-oxidant-enzymes (catalase,superoxide-dismutase) and lipid-peroxidation (LPO)respectively.Biochemical and Oxidative Stress Parameters and BodyWeight of the AnimalsBiochemical indices such as blood glucose, triglycerides,cholesterol, high density lipoproteins (HDL), plasma ureanitrogen and plasma creatinine were assayed on day 0(pretreatment), day 15 and day 29 (post treatment) usingkits (Erba, HP, India). However, low density lipoprotein(LDL) in plasma was estimated using the following for-mula [38]. LDL ð mg/dl) ¼ TC  HDL  TG = 5 : 0 ; where TC is the total cholesterol and TG is the triglyceridesTo detect any changes in body weight the animals wereweighed. The antioxidant enzymes superoxide dismutase(SOD) [39], catalase [40] and tissue damage biomarker LPO [41] were estimated in blood samples. 398 M. Ahmad et al.  1 3  Statistical AnalysisStatistical data analysis was done using analysis of vari-ance (ANOVA) which was carried out in completely ran-domized design (CRD) and the significance was testedusing Duncan Multiple Range Test [42] and the level of  significance was assayed at 5 % level ( P \ 0.05). Results and Discussion The percent alcoholic extractability of   S. cordifolia  was19.06 % (w/w) and extract revealed the presence of alka-loids, glycosides, saponins, sterols, resins, fixed oil andflavonoids. Kaur et al. [43] also reported similar percentextractability. The findings of phytochemicals were similarto the findings of Ghosal et al. [44], Guntilaka et al. [45], Kapoor [46], Sutradhar et al. [47], and Pawar et al. [48]. A significant increase in blood glucose level wasobserved in group II, III, IV and V diabetic rats on day 0 ascompared to group I control rats (Fig. 1). Treatment wasgiven to group IV diabetic rats with alcoholic extract of   S.cordifolia  at the dose of 400 mg/kg which produced asignificant decrease in blood glucose level on day 15 and29 as compared to day 0. The blood glucose level in groupIV and group V on day 29 decreased to the extent whichis comparable to control rats of group I, but the dose200 mg/kg was not enough to decrease blood glucose levelappreciably in group III diabetic rats. Although with gli-benclamide treatment, the blood glucose level in group Vdiabetic rats was significantly decreased and was compa-rable to group I control rats. Similar decrease in bloodglucose level was also reported at different doses of   S.cordifolia  [15, 21, 43]. The possible mechanism of hypo- glycemic activity of   S. cordifolia  may be through increasein glucose metabolism [43]. It has been reported thatmainly alkaloids and flavonoids are responsible for anincrease in insulin secretion and peripheral glucose utili-zation [49]. Diabetes is characterized with the loss of body weight asbody protein or fats are being utilized for energy generationthrough gluconeogenesis [50]. A significant decrease inbody weight was found in diabetic rats of group II on day 0and 29 as compared to rats before diabetic (pretreatment)within same group while in  S. cordifolia  (400 mg/kg) andglibenclamide treated diabetic rats of group IV and V, asignificant increase in body weight was found on day 29 ascompared to day 0 within the same group, respectively(Fig. 2). Although the dosage of   S. cordifolia  (200 mg/kg)used for diabetic rats of group III was not sufficient tocheck the decrease in body weight on day 29 as comparedto day 0. A significant improvement in body weight of diabetic rats indicated the possible role of extract inrestoration of protein metabolism which is supported byKaur et al. [43]. The ability of plant extract in restoration of body weight of diabetic rats may be through reversal of gluconeogenesis [51]. A significant decrease in triglyceride (Fig. 3), LDL(Fig. 4) and cholesterol levels (Fig. 5) were found on day 15 and 29 in group IV and V diabetic rats treated with plantextract at dose 400 mg/kg and glibenclamide as comparedto day 0 within the group, respectively and also comparableto control rats on day 29. While the dose 200 mg/kg of   S.cordifolia  given to group III diabetic rats showed nonsignificant change in triglyceride and cholesterol level onday 29 as compared to day 0.A significant increase in HDL level was observed ingroup IV and group V diabetic rats treated with plantextract at dose 400 mg/kg and glibenclamide on day 15 and29 as compared to day 0, respectively and comparable tocontrol rats on day 0 (Fig. 6). Although HDL level showednon-significant change in group III diabetic rats treated at200 mg/kg of plant-extract as compared to day 0. Diabetesaffects the fat management indicated by an increase in totalcholesterol, triglycerides and LDL, with decrease in HDLlevels [52–54]. Similarly, Kaur et al. [43] also reported ameliorative effect with aqueous extract of   S. cordifolia  atthe dose of 1,000 mg/kg. The hypo cholesterolemic effectof the plant may be due to overall inhibition of fatty acidsynthesis [43, 55]. The significant reduction of LDL levels, in  S. cordifolia  treated rats may be due to the activation of LDL receptors in hepatocytes thus reducing the serum LDLlevel or may be due to the inhibition of cholesterol syn-thesis pathway [56]. The effect of   S. cordifolia  extract todecrease triglycerides may be through increase of insulinlevels. Insulin activates the enzyme lipoprotein lipase andhydrolyses triglycerides and the deficiency in insulin,thereby causes hyper triglyceridemia [43].The diabetic hyperglycemia induces elevations of bloodcreatinine and urea levels which are considered as signifi-cant markers of renal dysfunction. A significant decrease inplasma-urea-nitrogen (Fig. 7) and plasma creatinine(Fig. 8) levels was observed on day 29 as compared to day0 in group IV diabetic rats treated with plant extract at400 mg/kg and also comparable to control rats of group I.Although the dose 200 mg/kg for group III diabetic ratsshowed non significant change in plasma urea nitrogen andplasma creatinine levels on day 29. However in group Vglibenclamide treated diabetic rats on day 29 a significantdecrease in plasma-urea-nitrogen and plasma-creatininelevels was found as compared to day 0 which is compa-rable to group I control rats. Similar to present findings,Makwana et al. [57] reported that the aqueous extract of   S.cordifolia  has nephro protective potential in nephrotoxicityinduced by gentamicin and cisplatin. The higher amount of glucose in blood makes the kidney to work more which Anti-Hyperglycemic, Anti-Hyperlipidemic and Antioxidant 399  1 3  Fig. 1  Effect of alcoholic-extract of   S. cordifolia  andglibenclamide on blood glucoselevel after oral administration indiabetic wistar-rats ( n  =  6). Capital superscript   ( alphabet  )indicates level of significancewithin the group.  Smallsuperscript   ( alphabet  ) indicateslevel of significance betweenthe groups Fig. 2  Effect of alcoholic-extract of   S. cordifolia  andglibenclamide on body-weightafter oral administration indiabetic wistar-rats ( n  =  6). Capital superscript   ( alphabet  )indicates level of significancewithin the group.  Smallsuperscript   ( alphabet  ) indicateslevel of significance betweenthe groups Fig. 3  Effect of alcoholic-extract of   S. cordifolia  andglibenclamide on triglycerideafter oral administration indiabetic wistar-rats ( n  =  6). Capital superscript   ( alphabet  )indicates level of significancewithin the group.  Smallsuperscript   ( alphabet  ) indicateslevel of significance betweenthe groups400 M. Ahmad et al.  1 3  Fig. 4  Effect of alcoholic-extract of   S. cordifolia  andglibenclamide on LDL levelsafter oral administration indiabetic wistar-rats ( n  =  6). Capital superscript   ( alphabet  )indicates level of significancewithin the group.  Smallsuperscript   ( alphabet  ) indicateslevel of significance betweenthe groups Fig. 5  Effect of alcoholic-extract of   S. cordifolia  andglibenclamide on cholesterollevel after oral administration indiabetic wistar-rats ( n  =  6). Capital superscript   ( alphabet  )indicates level of significancewithin the group.  Smallsuperscript   ( alphabet  ) indicateslevel of significance betweenthe groups Fig. 6  Effect of alcoholic-extract of   S. cordifolia  andglibenclamide on HDL levelafter oral administration indiabetic wistar-rats ( n  =  6). Capital superscript   ( alphabet  )indicates level of significancewithin the group.  Smallsuperscript   ( alphabet  ) indicateslevel of significance betweenthe groupsAnti-Hyperglycemic, Anti-Hyperlipidemic and Antioxidant 401  1 3
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