Download PDF
Drug Res (Stuttg) 2021; 71(07): 407-412
DOI: 10.1055/a-1508-5368
Original Article

Hepatoprotective Impact of Ghrelin against Cyclophosphamide-Induced Toxicity in the Male Mice

Elnaz Khordad
1   Department of Physiology, School of Paramedical Sciences, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
2   Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
,
Fatemeh Alipour
3   Department of Anatomy and Cellular Biology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
,
Mahdieh Pourabbas
4   Student Research Committee, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
,
Somaieh Mansouri
5   Department of Anatomy, Faculty of Medicine, North Khorasan University of Medical Sciences, Bojnurd, Iran
,
Ramin Salimnejad
6   Department of Anatomical Sciences and Pathology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
› Author Affiliations
› Further Information
Also available at
    Permissions and Reprints

Abstract

Background Despite its vast spectrum of clinical usage, cyclophosphamide (CP) exerts many adverse impacts, including hepatotoxicity. Antioxidant properties of ghrelin might protect the liver from CP-induced toxicity. The current study aimed to assess the protective impacts of ghrelin on CP-induced liver toxicity.

Methods Forty male mice were randomly divided into four groups (n=10) Group 1 as control received no intervention,group 2 received cyclophosphamide (CP) (100 mg/kg, i.p.) for five weeks and once a week. Group 3 received CP+ghrelin (CP+G), (80 µg/kg daily, i.p.) for five weeks. Group 4 received ghrelin with above-mentioned dose. At the end of the experiment, the mice were sacrificed to remove liver tissuesfor histological and biochemical examination.

Results Malondialdehyde (MDA) level increased after CP treatment but ghrelin administration significantly decreased the level of MDA (P<0.05). Measurement of the total antioxidant capacity (TAC) noted a significant decrease in the CP group against the control group (P<0.05). Ghrelin treatment in the CP+G group considerably increased the TAC activity when compared to the CP group (P<0.05). Histological examinations also confirmed the hepatocyte necrosis, local bleeding and inflammation, vacuolation, and sinusoidal dilation in the CP group, ghrelin administration reduced the destructive effects of CP on the liver significantly (P<0.05).

Conclusion Our results reveal the hepatoprotective effect of ghrelin against CP. Therefore, ghrelin might be useful in protecting the body against the adverse impacts of injuries induced by chemotherapeutic drugs.

Key words

Cyclophosphamide - Ghrelin - liver - Mice


Publication History

Received: 03 April 2021

Accepted: 10 May 2021

Article published online:
19 July 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Reference

  • 1 Control CfD, Prevention Cancer death rates--Appalachia, 1994-1998. MMWR Morbidity and Mortality Weekly Report 2002; 51: 527-529
    PubMedGoogle Scholar
  • 2 Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nature reviews Clinical Oncology 2009; 6: 638
    CrossrefPubMedGoogle Scholar
  • 3 Salimnejad R, Soleimani Rad J, Mohammad Nejad D. et al. Effect of ghrelin on total antioxidant capacity, lipid peroxidation, sperm parameters and fertility in mice against oxidative damage caused by cyclophosphamide. Andrologia. 2018; 50: e12883
    CrossrefPubMedGoogle Scholar
  • 4 More GS, Thomas AB, Chitlange SS. et al. Nitrogen mustards as alkylating agents: a review on chemistry, mechanism of action and current USFDA status of drugs. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents) 2019; 19: 1080-1102
    CrossrefPubMedGoogle Scholar
  • 5 Fraiser LH, Kanekal S, Kehrer JP. Cyclophosphamide toxicity. Drugs. 1991; 42: 781-795
    CrossrefPubMedGoogle Scholar
  • 6 Hamsa T, Kuttan G. Protective role of Ipomoea obscura (L.) on cyclophosphamide-induced uro-and nephrotoxicities by modulating antioxidant status and pro-inflammatory cytokine levels. Inflammopharmacology. 2011; 19: 155-167
    CrossrefPubMedGoogle Scholar
  • 7 Bhat N, Kalthur SG, Padmashali S. et al. Toxic effects of different doses of cyclophosphamide on live. Ethiopian Journal of Health Sciences. 2018 28.
    Google Scholar
  • 8 Shokrzadeh M, Ahmadi A, Naghshvar F. et al. Prophylactic efficacy of melatonin on cyclophosphamide-induced liver toxicity in mice. BioMed Research International. 2014 2014.
    Google Scholar
  • 9 Mohammad MK, Avila D, Zhang J. et al. Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress. Toxicology and Applied Pharmacology 2012; 265: 73-82
    CrossrefPubMedGoogle Scholar
  • 10 Stankiewicz A, Skrzydlewska E, Makieła M. Effects of amifostine on liver oxidative stress caused by cyclophosphamide administration to rats. Drug Metabolism and Drug Interactions 2002; 19: 67-82
    CrossrefPubMedGoogle Scholar
  • 11 Sánchez-Valle V, Chavez-Tapia N, Uribe M. et al. Role of oxidative stress and molecular changes in liver fibrosis: A review. Current Medicinal Chemistry 2012; 19: 4850-4860
    CrossrefPubMedGoogle Scholar
  • 12 Cichoż-Lach H, Michalak A. Oxidative stress as a crucial factor in liver diseases. World Journal of Gastroenterology: WJG 2014; 20: 8082
    CrossrefPubMedGoogle Scholar
  • 13 Li M, Zhu Q, Hu C. et al. Protective effects of eicosapentaenoic acid on genotoxicity and oxidative stress of cyclophosphamide in mice. Environmental toxicology 2011; 26: 217-223
    CrossrefPubMedGoogle Scholar
  • 14 Fouad AA, Qutub HO, Al-Melhim WN. Punicalagin alleviates hepatotoxicity in rats challenged with cyclophosphamide. Environmental Toxicology and Pharmacology 2016; 45: 158-162
    CrossrefPubMedGoogle Scholar
  • 15 Lin Y, Liang Z, He L. et al. Gut ghrelin regulates hepatic glucose production and insulin signaling via a gut-brain-liver pathway. Cell Communication and Signaling 2019; 17: 1-14
    CrossrefPubMedGoogle Scholar
  • 16 Moreno M, Chaves JF, Sancho-Bru P. et al. Ghrelin attenuates hepatocellular injury and liver fibrogenesis in rodents and influences fibrosis progression in humans. Hepatology. 2010; 51: 974-985
    CrossrefPubMedGoogle Scholar
  • 17 Salimnejad R, Rad JS, Nejad DM. Protective Effect of ghrelin on oxidative stress and tissue damages of mice testes followed by chemotherapy with cyclophosphamide. Crescent Journal of Medical and Biological Sciences 2018; 5: 138-143
    PubMedGoogle Scholar
  • 18 Wang W, Bansal S, Falk S. et al. Ghrelin protects mice against endotoxemia-induced acute kidney injury. American Journal of Physiology-Renal Physiology 2009; 297: F1032-F1037
    CrossrefPubMedGoogle Scholar
  • 19 Huang C-X, Yuan M-J, Huang H. et al. Ghrelin inhibits post-infarct myocardial remodeling and improves cardiac function through anti-inflammation effect. Peptides. 2009; 30: 2286-2291
    CrossrefPubMedGoogle Scholar
  • 20 Çetin E, Kanbur M, Çetin N. et al. Hepatoprotective effect of ghrelin on carbon tetrachloride-induced acute liver injury in rats. Regulatory Peptides 2011; 171: 1-5
    CrossrefPubMedGoogle Scholar
  • 21 Obay BD, Taşdemir E, Tümer C. et al. Dose dependent effects of ghrelin on pentylenetetrazole-induced oxidative stress in a rat seizure model. Peptides. 2008; 29: 448-455
    CrossrefPubMedGoogle Scholar
  • 22 Mazani M, Rezagholizadeh L, Shamsi S. et al. Protection of CCl4-induced hepatic and renal damage by linalool. Drug and Chemical Toxicology 2020; 1-9
    CrossrefPubMedGoogle Scholar
  • 23 Ali AHA. Hepatoprotective Effect of Green Tea Extract against Cyclophosphamide Induced Liver Injury in Albino Rats. Forensic Medicine and Anatomy Research. 2018; 6: 11-19
    CrossrefPubMedGoogle Scholar
  • 24 Hazrati A, Salimnejad R, Alipour M. et al. Protective effect of ghrelin on testicular damages caused by chronic hypoxia in rats: a histopathological study. Andrologia. 2018; 50: e12989
    CrossrefPubMedGoogle Scholar
  • 25 Yousefi H, Ahmadiasl N, Salimnejad R. et al. Effects of renal ischemia-reperfusion on biochemical factors and histopathological alterations in the liver of male rats. Physiol Pharmacol. 2019; 23 :44–50.
    Google Scholar
  • 26 Shokoohi M, Soltani M, Abtahi-Eivary S-H. et al. Effect of hydro--alcoholic extract of Olea europaea on apoptosis--related genes and oxidative stress in a rat model of torsion/detorsion--induced ovarian damage. Asian Pacific Journal of Reproduction 2019; 8: 148
    CrossrefPubMedGoogle Scholar
  • 27 Khan M, Sekhon B, Jatana M. et al. Administration of N-acetylcysteine after focal cerebral ischemia protects brain and reduces inflammation in a rat model of experimental stroke. Journal of Neuroscience Research 2004; 76: 519-527
    CrossrefPubMedGoogle Scholar
  • 28 El-Agamy DS, Elkablawy MA, Abo-Haded HM. Modulation of cyclophosphamide-induced cardiotoxicity by methyl palmitate. Cancer chemotherapy and pharmacology 2017; 79: 399-409
    CrossrefPubMedGoogle Scholar
  • 29 Ghafouri-Fard S, Shoorei H, Taheri M. Non-coding RNAs are involved in the response to oxidative stress. Biomedicine & Pharmacotherapy 2020; 127: 110228
    CrossrefPubMedGoogle Scholar
  • 30 Liberatore RA, Goff SP, Nunes I. NF-κB activity is constitutively elevated in c-Abl null fibroblasts. Proceedings of the National Academy of Sciences 2009; 106: 17823-17828
    CrossrefPubMedGoogle Scholar
  • 31 Asiri YA. Probucol attenuates cyclophosphamide-induced oxidative apoptosis, p53 and Bax signal expression in rat cardiac tissues. Oxidative Medicine and Cellular Longevity 2010; 3: 308-316
    CrossrefPubMedGoogle Scholar
  • 32 Zarei M, Shivanandappa T. Amelioration of cyclophosphamide-induced hepatotoxicity by the root extract of Decalepis hamiltonii in mice. Food and chemical toxicology 2013; 57: 179-184
    CrossrefPubMedGoogle Scholar
  • 33 Nelson S D, Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Seminars in liver disease.1990; 10: 267–78