The Potential Role ofAzadirachta indicaTreatment onCisplatin-Induced Hepatotoxicity and Oxidative Stressin Female Rats
Date
2013
Journal Title
Journal ISSN
Volume Title
Type
Article
Publisher
Hindawi
Series Info
Oxidative medicine and cellular longevity;
Doi
Scientific Journal Rankings
Abstract
Azadirachta indica A. Juss. (neem, family: Meliaceae) is perhaps the most commonly used traditional medicinal plant of India. In this study we investigated the protective effect of methanolic neem leaves extract (MNLE; 500 mg/Kg bwt) on rats treated with cisplatin (CDDP)-induced hepatotoxicity. Adult rats were randomly divided into four groups. CDDP was given to rats by intraperitoneal injection, while MNLE was given by oral gavage for 5 days after the CDDP injection. The injury and oxidative stress caused by CDDP on the liver and the effect of MNLE were evaluated by measuring (a) histological changes, (b) tissue biochemical oxidant and antioxidant parameters, and (c) investigating apoptosis markers immunohistochemically and by real time PCR. After treatment with MNLE, the histological damage and apoptosis induction caused by cisplatin were improved. Malondialdehyde and nitric oxide were significantly decreased; the antioxidant system, namely, glutathione content, glutathione-S-transferase, glutathione peroxidase, catalase, and superoxide dismutase activities were significantly elevated. In conclusion, MNLE may have a potential role when combined with cisplatin in chemotherapy to alleviate cisplatin-induced damage and oxidative stress in liver
Description
Keywords
University for Potential Role, Azadirachta, Hepatotoxicity, Female Rats
Citation
[1] M. A. Fuertes, J. Castilla, C. Alonso, and J. M. P ́erez, “Novelconcepts in the development of platinum antitumor drugs,”Current Medicinal Chemistry,vol.2,no.4,pp.539–551,2002.[2] G. T ̈urk, A. Ates ̧s ̧ahin, M. S ̈onmez, A. O. C ̧eribas ̧i, and A. Y ̈uce,“Improvement of cisplatin-induced injuries to sperm quality,the oxidant-antioxidant system, and the histologic structure ofthe rat testis by ellagic acid,”Fertility and Sterility,vol.89,no.5,supplement, pp. 1474–1481, 2008.[3]S.J.Lippard,“Newchemistryofanoldmolecule:cis-[Pt(NH3)2Cl2],”Science,vol.218,no.4577,pp.1075–1082,1982.[4] D. Wang and S. J. Lippard, “Cellular processing of platinumanticancer drugs,”Nature Reviews Drug Discovery,vol.4,no.4,pp. 307–320, 2005.[5] R. Pratibha, R. Sameer, P. V. Rataboli, D. A. Bhiwgade, and C. Y.Dhume, “Enzymatic studies of cisplatin induced oxidative stressin hepatic tissue of rats,”European Journal of Pharmacology,vol.532, no. 3, pp. 290–293, 2006.[6] Y. Lu and A. I. Cederbaum, “Cisplatin-induced hepatotoxicityis enhanced by elevated expression of cytochrome P450 2E1,”Toxicological Sciences,vol.89,no.2,pp.515–523,2006.[7] Y. I. Chirino and J. Pedraza-Chaverri, “Role of oxidative andnitrosative stress in cisplatin-induced nephrotoxicity,”Experi-mental and Toxicologic Pathology,vol.61,no.3,pp.223–242,2009.[8] Y. Sadzuka, Y. Shimizu, and Y. Takino, “Role of glutathione S-transferase isoenzymes in cisplatin-induced nephrotoxicity inthe rat,”Toxicology Letters,vol.70,no.2,pp.211–222,1994.[9] Y. Kawai, T. Nakao, N. Kunimura, Y. Kohda, and M. Gemba,“Relationship of intracellular calcium and oxygen radicals tocisplatin-related renal cell injury,”Journal of PharmacologicalSciences,vol.100,no.1,pp.65–72,2006.[10] J. Arakaki, M. Suzui, T. Morioka et al., “Antioxidative andmodifying effects of a tropical plantAzadirachta indica(Neem) 8Oxidative Medicine and Cellular Longevityon azoxymethane-induced preneoplastic lesions in the ratcolon,”Asian Pacific Journal of Cancer Prevention,vol.7,no.3,pp.467–471,2006.[11] National Research Council (U.S.),Board on Science and Tech-nology for International Development: Neem: A Tree for SolvingglobalProblems:ReportofanAdHocPaneloftheBoardonScience and Technology for International Development, NationalResearch Council, National Academy Press, Washington, DC,USA, 1992.[12] K. Biswas, I. Chattopadhyay, R. K. Banerjee, and U. Bandyopad-hyay, “Biological activities and medicinal properties of neem(Azadirachta indica),”Current Science,vol.82,no.11,pp.1336–1345, 2002.[13] M.A.Dkhil,S.Al-Quraishy,A.E.AbdelMoneim,andD.Delic,“Protective effect ofAzadirachta indicaextract against Eimeriapapillata-induced coccidiosis,”Parasitology Research,vol.112,no. 1, pp. 101–106, 2013.[14] S. Reitman and S. Frankel, “A colorimetric method for the deter-mination of serum glutamic oxalacetic and glutamic pyruvictransaminases,”American Journal of Clinical Pathology,vol.28,no. 1, pp. 56–63, 1957.[15] G. Szasz, “A kinetic photometric method for serum gamma-glutamyl transpeptidase,”Clinical Chemistry,vol.15,no.2,pp.124–136, 1969.[16] A. Belfield and D. M. Goldberg, “Revised assay for serum phenylphosphatase activity using 4-amino-antipyrine,”Enzyme,vol.12,no.5,pp.561–573,1971.[17] E. J. King and R. V. Coxon, “Determination of bilirubinwith precipitation of the plasma proteins,”Journal of ClinicalPathology,vol.3,pp.248–259,1950.[18] H. Ohkawa, N. Ohishi, and K. Yagi, “Assay for lipid peroxidesin animal tissues by thiobarbituric acid reaction,”AnalyticalBiochemistry,vol.95,no.2,pp.351–358,1979.[19] L. C. Green, D. A. Wagner, and J. Glogowski, “Analysis ofnitrate, nitrite, and [15N]nitrate in biological fluids,”AnalyticalBiochemistry,vol.126,no.1,pp.131–138,1982.[20] G. L. Ellman, “Tissue sulfhydryl groups,”Archives of Biochem-istry and Biophysics,vol.82,no.1,pp.70–77,1959.[21] M.Nishikimi,N.AppajiRao,andK.Yagi,“Theoccurrenceofsuperoxide anion in the reaction of reduced phenazine metho-sulfate and molecular oxygen,”Biochemical and BiophysicalResearch Communications, vol. 46, no. 2, pp. 849–854, 1972.[22] H. Aebi, “Catalase in vitro,”Methods in Enzymology,vol.105,pp.121–126, 1984.[23] D. E. Paglia and W. N. Valentine, “Studies on the quantitativeand qualitative characterization of erythrocyte glutathione per-oxidase,”The Journal of Laboratory and Clinical Medicine,vol.70,no.1,pp.158–169,1967.[24] V. M. Factor, A. Kiss, J. T. Woitach, P. J. Wirth, and S. S.Thorgeirsson, “Disruption of redox homeostasis in the trans-forming growth factor-𝛼�/c-myc transgenic mouse model ofaccelerated hepatocarcinogenesis,”Journal of Biological Chem-istry,vol.273,no.25,pp.15846–15853,1998.[25]D.DelRio,A.J.Stewart,andN.Pellegrini,“Areviewofrecent studies on malondialdehyde as toxic molecule andbiological marker of oxidative stress,”Nutrition, Metabolism andCardiovascular Diseases, vol. 15, no. 4, pp. 316–328, 2005.[26] C. T. D’Angio and J. N. Finkelstein, “Oxygen regulation ofgene expression: a study in opposites,”Molecular Genetics andMetabolism,vol.71,no.1-2,pp.371–380,2000.[27] S. Saleh and E. El-Demerdash, “Protective effects of L-arginineagainst cisplatin-induced renal oxidative stress and toxicity: roleof nitric oxide,”Basic and Clinical Pharmacology and Toxicology,vol.97,no.2,pp.91–97,2005.[28]S.Silici,O.Ekmekcioglu,M.Kanbur,andK.Deniz,“Theprotective effect of royal jelly against cisplatin-induced renaloxidative stress in rats,”World Journal of Urology,vol.29,no.1, pp. 127–132, 2011.[29] S. Takaki-Doi, K. Hashimoto, M. Yamamura, and C. Kamei,“Antihypertensive activities of royal jelly protein hydrolysateand its fractions in spontaneously hypertensive rats,”ActaMedica Okayama,vol.63,no.1,pp.57–64,2009.[30] P. Sithisarn, R. Supabphol, and W. Gritsanapan, “Antioxidantactivity of Siamese neem tree (VP1209),”Journal of Ethnophar-macology,vol.99,no.1,pp.109–112,2005.[31] R. R. Chattopadhyay, “Possible mechanism of hepatoprotectiveactivity ofAzadirachta indicaleaf extract: part II,”Journal ofEthnopharmacology,vol.89,no.2-3,pp.217–219,2003.[32] R. R. Chattopadhyay, S. K. Sarkar, S. Ganguly, R. N. Banerjee,T. K. Basu, and A. Mukherjee, “Hepatoprotective activity ofAzadirachta indicaleaves on paracetamol induced hepaticdamage in rats,”Indian Journal of Experimental Biology,vol.30,no. 8, pp. 738–740, 1992.[33] S. Bhanwra, J. Singh, and P. Khosla, “Effect ofAzadirachta indica(Neem) leaf aqueous extract on paracetamol-induced liverdamage in rats,”Indian Journal of Physiology and Pharmacology,vol.44,no.1,pp.64–68,2000.[34] A. Mallick, S. Ghosh, S. Banerjee et al., “Neem leaf glycoproteinis nontoxic to physiological functions of Swiss mice and SpragueDawley rats: histological, biochemical and immunological per-spectives,”International Immunopharmacology,vol.15,no.1,pp.73–83, 2013.[35]Y.Liao,X.Lu,C.Lu,G.Li,Y.Jin,andH.Tang,“Selectionof agents for prevention of cisplatin-induced hepatotoxicity,”Pharmacological Research,vol.57,no.2,pp.125–131,2008.[36] Y.T.Tarladacalisir,M.Kanter,andM.Uygun,“Protectiveeffectsof vitamin C on cisplatin-induced renal damage: a light andelectron microscopic study,”Renal Failure,vol.30,no.1,pp.1–8,2008.[37] A. Ates ̧s ̧ahin, I. Karahan, G. T ̈urk, S. G ̈ur,S.Yilmaz,andA.O. C ̧eribas ̧i, “Protective role of lycopene on cisplatin-inducedchanges in sperm characteristics, testicular damage and oxida-tive stress in rats,”Reproductive Toxicology,vol.21,no.1,pp.42–47, 2006.[38] H. I. El-Sayyad, M. F. Ismail, F. M. Shalaby et al., “Histopatho-logical effects of cisplatin, doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats,”International Journal ofBiological Sciences,vol.5,no.5,pp.466–473,2009.[39] A. Kart, Y. Cigremis, M. Karaman, and H. Ozen, “Caffeic acidphenethyl ester (CAPE) ameliorates cisplatin-induced hepato-toxicity in rabbit,”Experimental and Toxicologic Pathology,vol.62, no. 1, pp. 45–52, 2010.[40] P. Kupradinun, A. Tepsuwan, N. Tantasi, N. Meesiripun, A.Rungsipipat, and W. R. Kusamran, “Anticlastogenic and anti-carcinogenic potential of Thai bitter: gourd fruits,”Asian PacificJournal of Cancer Prevention,vol.12,no.5,pp.1299–1305,2011.[41]M.Dorababu,M.C.Joshi,G.Bhawani,M.M.Kumar,A.Chaturvedi, and R. K. Goel, “Effect of aqueous extract ofneem (Azadirachta indica) leaves on offensive and diffensivegastric mucosal factors in rats,”Indian Journal of Physiology andPharmacology,vol.50,no.3,pp.241–249,2006. Oxidative Medicine and Cellular Longevity9[42] R.C.Srivastava,A.Farookh,N.Ahmad,M.Misra,S.K.Hasan,and M. M. Husain, “Evidence for the involvement of nitric oxidein cisplatin-induced toxicity in rats,”BioMetals,vol.9,no.2,pp.139–142, 1996.[43] Y. Lu and A. I. Cederbaum, “Cisplatin-induced hepatotoxicityis enhanced by elevated expression of cytochrome P450 2E1,”Toxicological Sciences,vol.89,no.2,pp.515–523,2006.[44] M. Iraz, E. Ozerol, M. Gulec et al., “Protective effect ofcaffeic acid phenethyl ester (CAPE) administration on cisplatin-induced oxidative damage to liver in rat,”Cell Biochemistry andFunction,vol.24,no.4,pp.357–361,2006.[45] H. H. Mansour, F. Hafez, and N. M. Fahmy, “Silymarin mod-ulates cisplatin-induced oxidative stress and hepatotoxicity inrats,”Journal of Biochemistry and Molecular Biology,vol.39,no.6, pp. 656–661, 2006.[46] N.A.G.Santos,C.S.C.Bezerra,N.M.Martins,C.Curti,M.L. P. Bianchi, and A. C. Santos, “Hydroxyl radical scavengerameliorates cisplatin-induced nephrotoxicity by preventingoxidative stress, redox state unbalance, impairment of energeticmetabolism and apoptosis in rat kidney mitochondria,”CancerChemotherapy and Pharmacology,vol.61,no.1,pp.145–155,2008.[47]V.Lobo,A.Patil,A.Phatak,andN.Chandra,“Freeradicals,antioxidants and functional foods: impact on human health,”Pharmacognosy Reviews,vol.4,no.8,pp.118–126,2010.[48] N. I. Weijl, T. J. Elsendoorn, E. G. W. M. Lentjes et al., “Supple-mentation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-basedchemotherapy: a randomised, double-blind, placebo-controlledstudy,”European Journal of Cancer, vol. 40, no. 11, pp. 1713–1723,2004.[49] A. Karadeniz, N. Simsek, E. Karakus et al., “Royal jelly mod-ulates oxidative stress and apoptosis in liver and kidneys ofratstreatedwithcisplatin,”Oxidative Medicine and CellularLongevity,vol.2012,ArticleID981793,10pages,2012.[50] S. Bhattacharyya and P. Mehta, “The hepatoprotective potentialof Spirulina and vitamin C supplemention in cisplatin toxicity,”Food and Function,vol.3,no.2,pp.164–169,2012.[51] R. D. Hightower, B.-U. Sevin, J. P. Perras et al., “Comparisonof U-73,975 and cisplatin cytotoxicity in fresh cervical andovarian carcinoma specimens with the ATP-chemosensitivityassay,”Gynecologic Oncology,vol.47,no.2,pp.186–190,1992.[52] I. Hassan, S. Chibber, and I. Naseem, “Ameliorative effectofriboflavinonthecisplatininducednephrotoxicityandhepatotoxicity under photoillumination,”Food and ChemicalToxicology, vol. 48, no. 8-9, pp. 2052–2058, 2010.[53] R.D.Curran,F.K.Ferrari,P.H.Kispertetal.,“Nitricoxideandnitric oxide-generating compounds inhibit hepatocyte proteinsynthesis,”The FASEB Journal,vol.5,no.7,pp.2085–2092,1991.[54] Y. I. Chirino, J. Trujillo, D. J. S ́anchez-Gonz ́alez et al., “SelectiveiNOS inhibition reduces renal damage induced by cisplatin,”Toxicology Letters,vol.176,no.1,pp.48–57,2008.[55] S. C. Gangar and A. Koul, “Azadirachta indica modulatescarcinogen biotransformation and reduced glutathione at peri-initiation phase of benzo(a)pyrene induced murine forestom-ach tumorigenesis,”Phytotherapy Research,vol.22,no.9,pp.1229–1238, 2008.[56] N.M.Martins,N.A.G.Santos,C.Curti,M.L.P.Bianchi,andA. C. Dos Santos, “Cisplatin induces mitochondrial oxidativestress with resultant energetic metabolism impairment, mem-brane rigidification and apoptosis in rat liver,”Journal of AppliedToxicology,vol.28,no.3,pp.337–344,2008.[57] D. Ezz-Din, M. S. Gabry, A. R. H. Farrag, and A. E. AbdelMoneim, “Physiological and histological impact ofAzadirachtaindica(neem) leaves extract in a rat model of cisplatin-inducedhepato and nephrotoxicity,”Journal of Medicinal Plant Research,vol. 5, no. 23, pp. 5499–5506, 2011.[58] S. Jana and S. Mandlekar, “Role of phase II drug metab-olizing enzymes in cancer chemoprevention,”Current DrugMetabolism,vol.10,no.6,pp.595–616,2009.[59] P. Manikandan, S. M. Ramalingam, G. Vinothini et al., “Inves-tigation of the chemopreventive potential of neem leaf subfrac-tions in the hamster buccal pouch model and phytochemicalcharacterization,”European Journal of Medicinal Chemistry,vol.56, pp. 271–281, 2012.[60] S. Bedri, E. A. Khalil, S. A. Khalid et al., “Azadirachta indicaethanolic extract protects neurons from apoptosis and mitigatesbrain swelling in experimental cerebral malaria,”Malaria Jour-nal,vol.12,no.1,article298,2013.