PROTECTIVE EFFECTS OF GRAPE SEED EXTRACT (VITIS VINIFERA) AGAINST CISPLATIN- INDUCED LIVER DAMAGE IN RABBITS. (HISTOLOGICAL AND HISTOPATHOLOGICAL STUDY)

Abstract

Cisplatin is a chemotherapeutic drug used in the treatment of various cancer types. It can be considered a double-edged sword. It is a potent anticancer agent at the same time has toxic effect on various tissues as it causes hepatotoxicity. It was determined to cause liver toxicity and to weaken the antioxidant defense systems in liver. A decrease in antioxidant enzymes resulted from cisplatin induced tissue toxicity. Moreover, the development of therapies to prevent the appearance of cisplatin- induced tissue toxicities has focused on administration of antioxidants along with cisplatin treatment. The grape seeds exhibit a broad spectrum of pharmacological properties against oxidative stress. Therefore, the aim of present study was designed to investigate the protective effects of grape seed extract on the liver damage in cisplatin treated rabbits. Twenty seven healthy rabbits of local mixed breed were selected, divided into three equal groups, the first group (CON group) served as control and received a single intraperitoneal injection of normal saline solution once per week for 6 weeks; the second group (CIS group) were treated with therapeutic dose of cisplatin intraperitoneally once per week for six weeks; the third group (CIS+GSE group) served as protective group and was concomitantly treated with grape seeds extract by oral gavages and cisplatin injection intraperitoneally once per week for six successive weeks. Administration of grape seeds extract by oral gavages starting from the first day of the experiment for 6 consecutive days before and 6 consecutive days after the cisplatin injection and continued daily for 6 weeks.

The histopathological findings present in current study showed that cisplatin toxicity produced significant structural changes in the liver of CIS group , cisplatin treated group, in the form of prominent disorganized architecture and loss of liver lobulation, distortion of the arrangement of

 

parenchyma of the liver, loss of radial arrangement of sinusoids from the central vein of the liver, Dilatation and congestion of central veins, sinusoids and portal traids, degenerative changes in hepatocytes and pyknotic nuclei indicating necrosis. Marked vacuolar degeneration mainly hydropic ballooning degeneration and hyper activation of Kupffer cells and inflammatory cellular infiltrations were also observed. This finding reflected the cytotoxic effects of cisplatin in hepatic tissue. While, in the sections from the liver of animals received therapeutic dose of cisplatin and treated by grape seed extract, group (CIS+GSE) clearly showed that there was a significant alleviated hepatotoxicity, since histopathological changes were markedly less pronounced compared to animals treated with cisplatin alone. Therefore, and based on our findings, the grape seed extract contributes significantly to the improvement of histological alterations in rabbit liver caused by cisplatin.

Keywords:

Cisplatin, toxicity, grape seeds extract, liver , rabbits

References

Ahsan R., Islam M., Bulbul J.I., Musaddik A., Haque E. 2009. Hepatoprotective activity of methanol extract of some medicinal plants against carbon tetrachloride-induce hepatotoxicity in rats. Eur J Sci Res. 37(2):302–10.

Subramaniam S., Khan H.B.H., Elumalai N., Lakshmi S.Y.S. 2015. Hepatoprotective effect of ethanolic extract of whole plant of Andrographis paniculata against CCl4-induced hepatotoxicity in rats. Comp Clin Path. 24:1-7

Abou-Seif H. S. 2016. Physiological changes due to hepatotoxicity and the protective role of some medicinal plants .J. of basic and applied sciences. 5: 134-146.

Friedman M. 2007. Overview of antibacterial, antitoxin, antiviraland antifungal activities of tea flavonoids and teas. Mol Nutr Food Res. 51:116–34.

Krishnamurthy B. S. 2010. Cellular responses to cisplatin-induced DNA damage. J. Nucleic Acids 1–16.

Dasari S., Tchounwou P.B. 2014. Cisplatin in cancer therapy: molecular mechanisms of action, Eur. J. Pharmacol. 740: 364–378.

Crisafuli F. P., Cesconetto E.C., Ramos E.B. and Rocha M.S. 2012. DNA–cisplatin interaction studied with single molecule stretching experiments, Integr. Biol. 4 : 568–574.

Bunel V., Tournay Y., Baudoux T., De Prez E., Marchand M., Mekinda Z., Marechal R., Roumeguere T., Antoine M.H., Nortier J.L. 2017. Early detection of acute cisplatin nephrotoxicity: interest of urinary monitoring of proximal tubular biomarkers, Clin. Kidney J. 10: 639–647

Al-Malki A. Sayed. 20 14. Thymoquinone attenuates cisplatin-induced hepatotoxicity via Nuclear Factor Kappa- β, BMCComplement. Altern. Med. 14: 1–8.

Hu B., Sun B., Zhao D, .Mei Q., Gu Z. and Tian E. 2018. Cisplatin-induced cardiotoxicity with midrange ejection fraction: a casereport and review of the literature, Med. (U. S.) 97: 13807.

Yu W., Chen Y., Dubrulle J., Stossi F., Putluri V., Sreekumar A., Putluri N., Baluya D., Lai S.Y., Sandulache V.C. 2018. Cisplatin generates oxidative stress which is accompanied by rapid shifts in central carbon metabolism,Sci. Rep. 8: 1–12.

Pratibha R., Sameer R., Rataboli P.V., Bhiwgade D.A., Dhume C.Y. 2006. Enzymatic studies of cisplatin induced oxidativestress in hepatic tissue of rats, Eur. J. Pharmacol. 532: 290–293.

Singh N., Magotra R., Sharma A.K., Ahmed M., Khajuria V. 2015. Effect of cisplatin on liver of male albino rats, J. Evol. Med. Dent. Sci. 4: 8993–8998,

Metri K., Bhargav H., Chowdhury P., Koka P.S. 2013. Ayurveda for chemo-radiotherapy induced side effects in cancer patients, J. Stem Cell. 8: 115–12.

GuptaY.K., Sharma M .,Chaudhary G. and Katiyar C.K. 2014. Hepatoprotective effect of New Livfit, a polyherbal formulation, is mediated through its freeradical scavenging activity.

Phytother.Res. 1:362–364.

Sandur S.K., Ichikawa H., Pandey M.K., Kunnumakkara A.B., Sung B., Sethi G.,

et al. 2007. Role of prooxidants and antioxidants in the anti-inflammatory and apoptotic effects of curcumin (diferuloylmethane). Free Radic Biol Med. 43:568–80.

Georgiev V., Ananga A., Tsolova V. 2014. Recent advances and uses of grapeflavonoids as nutraceuticals. Nutrients. 6(1):391–415.

Ali K., Maltese F., Choi Y.H., et al. 2010. Metabolic constituents of grapevine and grape derived products. Phytochem Rev. 9(3):357–378.

Bagchi D., Garg A., Krohn R.L., Bagchi M., Bagchi D.J., Balmoori J., Stohs S.J. 1998. Protective effects of grape seed proanthocyanidins and selected antioxidants against TPA-induced hepatic and brain lipid peroxidation and DNA fragmentation,and peritoneal macrophage activation in mice, Gen. Pharmacol. 30: 771–776.

Yamakoshi J., Saito M., Kataoka S., Kikuchi M. 2002. Safety evaluation of proanthocyanidin- rich extract from grape seeds,Food Chem. Toxicol. 40: 599–607.

Huang S., Yang N., Liu Y., et al. 2012. Grape seed proanthocyanidins inhibit colon cancer- induced angiogenesis through suppressing the expression of VEGF and Ang1. Int J Mol. Med. 30(6):1410–1416. doi: 10.3892/ijmm.2012.1147.

Zhang X.Y., Bai D.C., Wu Y.J., Li W-G, Liu N.F. 2005. Proanthocyanidin from grape seeds enhances anti-tumor effect of doxorubicin both in vitro and in vivo. Pharmazie. 60(7):533-538.

Yousef M. I., Saad A. A. and El-Shennawy L. K. 2009. Protective effect of grape seed proanthocyanidin extract against oxidative stress induced by cisplatin in rats. FoodChem Toxicol. Jun. 47(6):1176-1183S

Yuemei Du, Yunfan Liu, Zhang Hailian, Zhao Yanmeng and Liping Gao.2021. Effects of grape seed proanthocyanidin extract on cisplatin-Induced renal oxidative damage and apoptosis in rats.

Pharmacognosy magazine. 17, 75 : 460-467.

Okoko T. and Oruambo I.F. 2008. The effect of Hibiscus sabdariffa calyx extract on cisplatin- induced tissue damage in rats. Biokem. 20, 47-52.

Koga T., Moro K., Nakamori K., Yamakoshi J., Hosoyama H., Kataoke S. and Ariga T. 1999. Increase of antioxidative potential of rat plasma by oral administration of proanthocyanidin-rich extract from grape seeds. J. Agric. Food Chem. 47, 1892-1897.

Suvarna S. K., Layton C. & Bancroft J.D. 2019. Bancroft’s theory and practice of histological techniques. 8th Ed. Elsevier Limited.

Neamatallah T., El-Shitany N.A., Abbas A.T., Ali S.S., Eid B.G. 2018. Honey protects against cisplatin-induced hepatic and renal toxicity through inhibition of NFjB- mediated COX-2 expression and the oxidative stress dependent BAX/Bcl- 2/caspase-3 apoptotic pathway. Food Funct. 9 (7): 3743–3754.

Yadav Y.C. 2019. Effect of cisplatin on pancreas and testes in Wistar rats: biochemical parameters and histology. Heliyon. 5 (8): e02247

Hassan H., Al-Wahaibi L., Elmorsy M., Mahran Y. 2020. Suppression of Cisplatin- Induced Hepatic Injury in Rats Through Alarmin High-Mobility Group Box-1 Pathway by Ganoderma lucidum: Theoretical and Experimental Study. Drug Des Development Therapy. 14: 2335–2353. 31.Ishikawa T. 2009. Future perspectives on the treatment of hepatocellular carcinoma with cisplatin. World J Hepatol. 1 (1):8-16.

Omar H.A., Mohamed W.R., Arab H.H., Arafa E.-S.and Acharya K. 2016. Tangeretin Alleviates Cisplatin-Induced Acute Hepatic Injury in Rats: Targeting MAPKs and Apoptosis. Plos One. 11 (3): e0151649.

Galadari S., Rahman A., Pallichankandy S. and Thayyullathil F. 2017. Reactive oxygen species and cancer paradox: To promote or to suppress? Free Radical Biol. Med. 104: 144–164.

Mora L.O., Antunes L.M., Francescato H.D. and Bianchi M. 2003. The effects of oral glutamine on cisplatin-induced nephrotoxicity in rats. Pharmacol. Res. 47:517- 522.

Behling E.B., Sendao M.C., Francescato H.D., Antunes L.M., Costa R.S. and Bianchi- Mde, L. 2006. Comparative study of multiple dosage of quercetin against cisplatin- induced nephrotoxicity and oxidative stress in rat kidneys. Pharmacol. Rep. 58:526- 532

Aboulgasem G.J.A., Azab A.E. and Almaky M.M. 2015. Sodium nitrite induced biochemical alterations in the blood serum and its amelioration by aqueous extract of Libyan propolis in Guinea pigs. Inter J Sci Res. 4(8): 1040-1048.

Glinsukon T., et al., 1986. Acute toxicity of nimbolide and nimbic acid in mice, rats and hamsters. Toxicology Letters. 30 (2): 159–166.

Kamer E., et al., 2003. Effects of intraperitoneal administration of gemcitabine and paclitaxel on hepatic regeneration in rats. The Turkish Journal of Gastroenterology 14 (1): 1–6.

Leite E.A., Giuberti C. S., Wainstein A.J., Wainstein A.P., Coelho L.G., Lana A.M., Savassi

R. R. and De Oliveira M.C. 2009. Acute toxicity of long-circulating and pH-sensitive liposomes containing cisplatin in mice after intraperitoneal administration. Life Sci. May 8;84 (19- 20):641-9. 40.Rickenbacher A., et al., 2011. Arguments against toxic effects of chemotherapy on liver injury and regeneration in an experimental model of partial hepatectomy. Liver International. 31 (3): 313–321.

Hesham A.A., Ghobara M.M. 2013. Histological study of the effect of cisplatin on the liver of adult male albino rat,Int. J. Acad. Sci. Res. 1: 22–33.

Aboraya D.M. , El Baz A., Risha E.F. and Abdelhamid F.M.. 2022. Hesperidin ameliorates cisplatin induced hepatotoxicity and attenuates oxidative damage, cell apoptosis, and inflammation in rats. Saudi Journal of Biological Sciences. 29:3157–3166

Ragaa M.Abdel- Maaboud; Manal M. Shehata and Safaa A. Abdel- Maksoud. 2003. Histological Changes In Kidney And Liver Of The Rabbit As A Result Of The Use Of Kohl. AAMJ, April, Vol. 1, No. 2: 9-24.

Al-Hamdany M.Z. 2019. Comparative anatomical, histological, and histochemical study of liver in human and domestic rabbit. Iraqi Journal of Veterinary Sciences. Vol. 33, No. 2: 437-446.

Eyhab R. Al-samawy , Noora A. Hassan ,Mustafa Salah Hasan, Hawraa faisal Mshal. 2022. Histological study of the liver cells in rabbits (Review subject). Journal of Cardiovascular Disease Research. Vol.13,05: 3048.

El- Sayyad H.I., Ismail M., Shalaby F.M., Abou-El-Magd R.F. and Gaur R.L. 2009. Histopathological effects of Cisplatin, Doxorubicin and 5- flurouracil (5-FU) on the liver of male albino rats. Int.J.Biol.Sci. 5: 466- 473

Asim Kart, Yilmaz Cigremis, Musa Karaman, Hasan Ozen . 2010. Caffeic acid phenethyl ester (CAPE) ameliorates cisplatin-induced hepatotoxicity in rabbit. Exp Toxicol Pathol. Jan;62(1):45- 52.

Ali Karadeniz, Nejdet Simsek, Emre Karakus, Serap Yildirim, Adem Kara, Ismail Can, Fikrullah Kisa, Habib Emr and Mehmet Turkeli. 2011. Royal Jelly Modulates Oxidative Stress and Apoptosis in Liver and Kidneys of Rats Treated with Cisplatin. Oxid Med Cell Longev. 981793.

Kandemir F. M., Benzer F., Ozkaraca M., Ceribasi S., Cikcikoglu Yildirim N., Ozdemir N. 2012. Protective antioxidant effects of grape seed extract in a cisplatin-induced hepatotoxicity model in rabbits. Revue Méd. Vét. 163, 11 : 539-545.

Mir M., Arab M. R.,.Shahraki M. R, Mashhadi M. A., Salar M. S., Aval F. S., Karimfar M. H.

.Toxic Effects of Cisplatin on Hepatocytes and Liver Enzymes of Rats. Anatomical sciences. 2015. Vol. 12, Number 4.

Abdelmeguid N.E., Chmaisse H.N., Abdou Zeinab N.S. and Moharram B. Silymarin. 2010. ameliorates Cisplatin-induced hepatotoxicity in rats:Histopathological and Ultrastructure Studies. Pakistan journal of Biological Sciences. 13(1):463- 479.

Attyah M. A.and Ismail S. H. 2012. Protective Effect of Ginger Extract Against Cisplatin- Induced Hepatotoxicity and Cardiotoxicity in Rats. Iraqi J Pharm Sci . Vol.21(1).

Robbins S.L. and Angell M. 1976. Basic Pathology 2nd Ed. W.B. Saunders Company, Phildelphia, London.

Nasr A.Y. 2013. Morphological, biochemical, histological, and ultrastructural protective effects of misoprostol on cisplatin induced-hepatotoxicity in adult male rats. Saudi Medical Journal. 34: 1237–1247.

Alejandra Cano Paniagua and Pedro Amariles. 2018. Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors. 5: 77-92.

Johar D., Roth J.C., Bay G.H., Walker J.N., Kroczak T.J. and Los M. 2004. Inflammatory response, reactive oxygen species, programmed (necrotic-like and apoptotic) cell death and cancer. Rocz Akad Med Bialymst. 49: 31-39.

Işeri S., Ercan F., Gedik N., Yüksel M. and Alican İ. 2007. Simvastatin attenuates cisplatin- induced kidney and liver damage in rats. Toxicology. 230 : 256–264

Liao Y., Lu X., Lu C., Li G., Jin Y., and Tang H. 2008. Selection of agents for prevention of cisplatin-induced hepatotoxicity. Pharmacol Res. 57: 125–131.

Bagchi D., Bagchi M., Stohs S.J., Ray S.D., Sen C.K., Pruess H.G. 2002. Cellular protection with proanthocyanidins derived from grape seeds. Ann New York Acad Sci. 957:260–270.

Nurhan Unusan. 2020. Proanthocyanidins in grape seeds: An updated review of their health benefits and potential uses in the food industry. Journal of Functional Foods 67.

Xu Z.C., Yin J., Zhou B., et al. 2015. Grape seed proanthocyanidin protects liver against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress. World J Gastroenterol. 21(24):7468–7477

Hamza A.A., Heeba G. H., Elwy H.N., Murali C. , El-Awady R., Amin A.2018 . Molecular characterization of the grape seeds extract's effect against chemically induced liver cancer: In vivo and in vitro analyses. Jan; 8(1):1270.

Lenka Sochorova , Bozena Prusova , Martina Cebova, Tunde Jurikova , Jiri Mlcek , Anna Adamkova , Sarka Nedomova , Mojmir Baron and Jiri Sochor.2020. Health Effects of Grape Seed and Skin Extracts and Their Influence on Biochemical Markers. Molecules, 25: 5311.

Dif A., Mokhtaria Yasmina B., Ammam A. and Slimani M. 2022. Chemical composition and protective effect of anacyclus valentinus against cisplatin-induced hepatotoxicity in wistar

rats. Journal of microbiology, biotechnology and food sciences. 11: 6

Madhavi Gupta, SanjayDey, DaphishaMarbaniang, Paulami Pal, Subhabrata Ray and Bhaskar Mazumder. 2020. Grape seedextract: having a potential health benefits. J Food Sci Technol. Apr; 57(4): 1205–1215

Brunton LL, Lazo JS, Parker KI. 2006. Goodman and Gilman’s the pharmacological basis of therapeutics. New York: Mc Graw Hill Companies.

Salam O.M., Sleem A.A., Omara E.A., Hassan N.S. 2009. Hepatoprotective effects of misoprostol and silymarin on carbon tetrachloride-induced hepatic damage in rats. Fundam Clin Pharmacol 23: 179-188.

Nuria G., Acisclo P.M., Mercedes F., Jose M,;Patricio F. S. and Jose A. E. 2008. Cisplatin- mediated impairment of mitochondrial DNA metabolism inversely correlates with glutathione levels. Biochem. J. 414: 93- 102.

Amany A. Tohamy, Ahmed M. Aref, Ahmed E. Abdel Moneim, and Romissaa H. Sayed. 2016.Cinnamic acid Attenuates Cisplatin Induced Hepatotoxicity and Nephrotoxicity. Journal of Basic and Environmental Sciences 3 ) 1.(: 1– 9.