Skip to main content
Log in

Agmatine protects rat liver from nicotine-induced hepatic damage via antioxidative, antiapoptotic, and antifibrotic pathways

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Tobacco smoking with its various forms is a global problem with proved hazardous effects to human health. The present work was planned to study the defending role of agmatine (AGM) on hepatic oxidative stress and damage induced by nicotine in rats. Thirty-two rats divided into four groups were employed: control group, nicotine-only group, AGM group, and AGM-nicotine group. Measurements of serum hepatic biochemical markers, lipid profile, and vascular cell adhesion molecule-1 were done. In addition, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione (GSH) activity, and nitrate/nitrite (NOx) levels were estimated in the liver homogenates. Immunohistochemistry for Bax and transforming growth factor beta (TGF-β1) and histopathology of the liver were also included. Data of the study demonstrated that nicotine administration exhibited marked liver deterioration, an increase in liver enzymes, changes in lipid profile, and an elevation in MDA with a decline in levels of SOD, GSH, and NOx (nitrate/nitrite). Also, levels of proapoptotic Bax and profibrotic TGF-β1 showed marked elevation in the liver. AGM treatment to rats in nicotine-only group ameliorated all the previous changes. These findings indicate that AGM could successfully overcome the nicotine-evoked hepatic oxidative stress and tissue injury, apoptosis, and fibrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abe K, Abe Y, Saito H (2000) Agmatine suppresses nitric oxide production in microglia. Brain Res 872:141–148

    Article  CAS  PubMed  Google Scholar 

  • Arndt MA, Battaglia V, Parisi E, Lortie MJ, Isome M, Baskerville C, Pizzo DP, Ientile R, Colombatto S, Toninello A, Satriano J (2009) The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis. Am J Physiol Cell Physiol 296:C1411–C1419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bhutada P, Mundhada Y, Humane V, Rahigude A, Deshmukh P, Latad S, Jain K (2012) Agmatine, an endogenous ligand of imidazoline receptor protects against memory impairment and biochemical alterations in streptozotocin-induced diabetic rats. Prog Neuro-Psychopharmacol Biol Psychiatry 37:96–105

    Article  CAS  Google Scholar 

  • Chattopadhyay K, Chattopadhyay BD (2008) Effect of nicotine on lipid profile, peroxidation & antioxidant enzymes in female rats with restricted dietary protein. Indian J Med Res 127:571–576

    CAS  PubMed  Google Scholar 

  • Condello S, Currò M, Ferlazzo N, Caccamo D, Satriano J, Ientile R (2011) Agmatine effects on mitochondrial membrane potential and NF-κB activation protect against rotenone-induced cell damage in human neuronal-like SH-SY5Y cells. J Neurochem 116:67–75

    Article  CAS  PubMed  Google Scholar 

  • Das SK, Mukherjee S, Vasudevan DM (2010) Effects of long-term ethanol consumption on adhesion molecules in liver. Indian J Exp Biol 48:394–401

    CAS  PubMed  Google Scholar 

  • Dasgupta P, Rizwani W, Pillai S, Kinkade R, Kovacs M, Rastogi S, Banerjee S, Carless M, Kim E, Coppola D, Haura E, Chellappan S (2009) Nicotine induces cell proliferation, invasion and epithelial-mesenchymal transition in a variety of human cancer cell lines. Int J Cancer 124:36–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dey SK, Roy S (2010) Role of reduced glutathione in the amelioration of nicotine-induced oxidative stress. Bull Environ Contam Toxicol 84:385–389

    Article  CAS  PubMed  Google Scholar 

  • El-Zayadi AR (2006) Heavy smoking and liver. World J Gastroenterol 12:6098–6101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma without use of the preparative ultracentrifugation. Clin Chem 18:499–500

    CAS  PubMed  Google Scholar 

  • Ghaly MA, Khedr ES, Aleem AA (2002) A comparative study of nicotine effect on the liver of albino rat [J]. Egyptian J Hospital Med 10:130–144

    Google Scholar 

  • Guesdon JL, Ternynck T, Avrameas S (1979) The use of avidin biotin interaction in immunoenzymatic techniques. J Histochem Cytochem 27:1131–1139

    Article  CAS  PubMed  Google Scholar 

  • Guo Y, Mishra A, Howland E, Zhao C, Shukla D, Weng T, Liu L (2015) Platelet-derived Wnt antagonist Dickkopf-1 is implicated in ICAM-1/VCAM-1-mediated neutrophilic acute lung inflammation. Blood 126:2220–2229

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Han N, Yu L, Song Z, Luo L, Wu Y (2015) Agmatine protects Müller cells from high-concentration glucose-induced cell damage via N-methyl-D-aspartic acid receptor inhibition. Mol Med Rep 12:1098–1106

    CAS  PubMed  PubMed Central  Google Scholar 

  • Helen A, Krishnakumar K, Vijayammal PL, Augusti KT (2000) Antioxidant effect of onion oil (Allium cepa Linn.) on thedamages induced by nicotine in rats as compared to alpha-tocopherol. Toxicol Lett 116:61–68

    Article  CAS  PubMed  Google Scholar 

  • Hukkanen J, Jacob P, Benowitz NL (2005) Metabolism and disposition kinetics of nicotine. Pharmacological Rev 57:79–115

    Article  CAS  Google Scholar 

  • Husain K, Scott BR, Reddy SK, Somani SM (2001) Chronic ethanol and nicotine interaction on rat tissue antioxidant defense system. Alcohol 25:89–97

    Article  CAS  PubMed  Google Scholar 

  • Ivey R, Desai M, Green K, Sinha-Hikim I, Friedman TC, Sinha-Hikim AP (2014) Additive effects of nicotine and high-fat diet on hepatocellular apoptosis in mice: involvement of caspase 2 and inducible nitric oxide synthase-mediated intrinsic pathway signaling. Horm Metab Res 46:568–573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jensen K, Marzioni M, Munshi MK, Afroze S, Alpini G, Glaser S (2012) Autocrine regulation of biliary pathology by activated cholangiocytes. Am J PhysiolGastrointest Liver Physiol 302:G473–G483

    Article  CAS  Google Scholar 

  • Jha P, Ramasundarahettige C, Landsman V, Rostron B, Thun M, Anderson RN, McAfee T, Peto R (2013) 21st-century hazards of smoking and benefits of cessation in the United States. N Engl J Med 368:341–350

    Article  CAS  PubMed  Google Scholar 

  • Kim JH, Lee YW, Park YM, Park KA, Park SH, Lee WT, Lee JE (2011) Agmatine-reduced collagen scar area accompanied with surface righting reflex recovery after complete transection spinal cord injury. Spine (Phila Pa 1976) 36:2130–2138

    Article  Google Scholar 

  • Kim JM, Lee JE, Cheon SY, Lee JH, Kim SY, Kam EH, Koo BN(2015) The anti-inflammatory effects of agmatine on transient focal cerebral ischemia in diabetic rats. J Neurosurg Anesthesiol

  • Lee GT, Cho YD (2004) Regulation of fibronectin levels by agmatine and spermine in mesangial cells under high-glucose conditions. Diabetes Res ClinPract 66:119–128

    Article  CAS  Google Scholar 

  • Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501

    Article  CAS  PubMed  Google Scholar 

  • McCue JM, Link KL, Eaton SS, Freed BM (2000) Exposure to cigarette tar inhibits ribonucleotide reductase and blocks lymphocyte proliferation. J Immunol 165:6771–6775

    Article  CAS  PubMed  Google Scholar 

  • Molderings GJ, Haenisch B (2011) Agmatine (decarboxylated L-arginine): physiological role and therapeutic potential. Pharmacol Ther 133:351–365

    Article  CAS  PubMed  Google Scholar 

  • Moretti M, Matheus FC, de Oliveira PA, Neis VB, Ben J, Walz R, Rodrigues AL, Prediger RD (2014) Role of agmatine in neurodegenerative diseases and epilepsy. Front Biosci (Elite Ed) 6:341–359

    Article  Google Scholar 

  • Morley BJ, Garner LL (1990) Light-dark variation in response to chronic nicotine treatment and the density of hypothalamic alpha-bungarotoxin receptors. Pharmacol Biochem Behav 37:239–245

    Article  CAS  PubMed  Google Scholar 

  • Moszczyński P, Zabiński Z, Moszczyński P, Rutowski J, Słowiński S, Tabarowski Z (2001) Immunological findings in cigarette smokers. Toxicol Lett 118:121–127

    Article  PubMed  Google Scholar 

  • Nader MA, Gamiel NM, El-Kashef H, Zaghloul MS (2016) Effect of agmatine on experimental vascular endothelial dysfunction. Hum ExpToxicol 35:573–582

    Article  CAS  Google Scholar 

  • National research Council of the national academies (2011): The national academies press. Washington, D.C. 20055(800):624–6242

  • Neogy S, Das S, Mahapatra SK, Mandal N, Roy S (2008) Amelioratory effect of Andrographis paniculata Nees on liver, kidney, heart, lungs and spleen during nicotine induced oxidative stress [J]. Environ Toxicol Pharmacol 25:321–328

    Article  CAS  PubMed  Google Scholar 

  • Neurath GB (1994) Aspects of the oxidative metabolism of nicotine. Clin Invest 72:190–195

    Article  CAS  Google Scholar 

  • Peters H, Daig U, Martini S, Rückert M, Schäper F, Liefeldt L, Krämer S, Neumayer HH (2003) NO mediates antifibrotic actions of L-arginine supplementation following induction of anti-thy1 glomerulonephritis. Kidney Int 64:509–518

    Article  CAS  PubMed  Google Scholar 

  • Piletz JE, Aricioglu F, Cheng JT, Fairbanks CA, Gilad VH, Haenisch B, Halaris A, Hong S, Lee JE, Li J, Liu P, Molderings GJ, Rodrigues AL, Satriano J, Seong GJ, Wilcox G, Wu N, Gilad GM (2013) Agmatine: clinical applications after 100 years in translation. Drug Discov Today 18(17–18):880–893

    Article  CAS  PubMed  Google Scholar 

  • Pushpavalli G, Kalaiarasi V, Veeramani C, Pugalendi KV (2010) Effect of chrysin on hepatoprotective and antioxidant status in D galactosamine-induced hepatitis in rats. Eur J Pharmacol 631:36–41

    Article  CAS  PubMed  Google Scholar 

  • Regunathan S, Reis DJ (2000) Characterization of arginine decarboxylase in rat brain and liver: distinction from ornithine decarboxylase. J Neurochem 74:2201–2208

    Article  CAS  PubMed  Google Scholar 

  • Ryan CJ, Aslam M, Courtney JM (1990) Transference of hepaticcoma to normal rats from galactosamine treated donors by protective effects of agmatine against D-galactosamine reverse plasma exchange. Biomater Artif Cells Artif Organs 18:477–482

    Article  CAS  PubMed  Google Scholar 

  • Sanz AB, Santamaría B, Ruiz-Ortega M, Egido J, Ortiz A (2008) Mechanisms of renal apoptosis in health and disease. J Am Soc Nephrol 19:1634–1642

    Article  CAS  PubMed  Google Scholar 

  • Satriano J, Schwartz D, Ishizuka S, Lortie MJ, Thomson SC, GabbaiF KCJ, Blantz RC (2001) Suppression of inducible nitric oxide generation by agmatine aldehyde: beneficial effects in sepsis. J Cell Physiol 188:313–320

    Article  CAS  PubMed  Google Scholar 

  • Shan H, Zhang Y, Lu Y, Zhang Y, Pan Z, Cai B, Wang N, Li X, Feng T, Hong Y, Yang B (2009) Downregulation of miR-133 and miR-590 contributes to nicotine-induced atrial remodelling in canines. Cardiovasc Res 83:465–472

    Article  CAS  PubMed  Google Scholar 

  • Shaw M, Mitchell R, Dorling D (2000) Time for a smoke? One cigarette reduces your life by 11 min [J]. BMJ 320:53–59

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sheng HP, Yuen ST, So HL, Cho CH (2001) Hepatotoxicity of prenatal and postnatal exposure to nicotine in rat pups [J]. Exp Biol Med 226:934–939

    CAS  Google Scholar 

  • Solak ZA, Kabaroglu C, Cok G, Parildar Z, Bayindir U, Ozmen D, Bayindir O (2005) Effect of different levels of cigarette smoking on lipid peroxidation, glutathione enzymes and paraoxonase 1 activity in healthy people. Clin Exp Med 5:99–105

    Article  CAS  PubMed  Google Scholar 

  • Sreekala S, Indira M (2009) Effects of exogenous selenium on nicotine-induced oxidative stress in rats. Biol Trace Elem Res 130:62–71

    Article  CAS  PubMed  Google Scholar 

  • Talhout R, Schulz T, Florek E, Van Benthem J, Wester P, Opperhuizen A (2011) Hazardous compounds in tobacco smoke. Int J Environ Res Public Health 8:613–628

    Article  PubMed  PubMed Central  Google Scholar 

  • Tamm C, Zhivotovsky B, Ceccatelli S (2008) Caspase-2 activation in neural stem cells undergoing stress-induced apoptosis. Apoptosis 13:354–363

    Article  CAS  PubMed  Google Scholar 

  • Thompson CB (1995) Apoptosis in the pathogenesis and treatment of disease. Science 267:1456–1462

    Article  CAS  PubMed  Google Scholar 

  • Thun MJ, Carter BD, Feskanich D, Freedman ND, Prentice R, Lopez AD, Hartge P, Gapstur SM (2013) 50-year trends in smoking-related mortality in the United States. N Engl J Med 368:351–364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tracy WR, Tse J, Carter G (1995) Lipopolysaccharide-induced changes in plasma nitrate and nitrite concentration in rats and mice: pharmacological evaluation of nitric oxide synthase inhibitors. J Pharmacol Exp Ther 272:1011–1015

    Google Scholar 

  • Valenca SS, Gouveia L, Pimenta WA, Porto LC (2008) Effects of oral nicotine on rat liver stereology. Int J Morphol 26:1013–1022

    Article  Google Scholar 

  • Watkins SS, Koob GF, Markou A (2000) Neural mechanisms underlying nicotine addiction: acute positive reinforcement and withdrawal. Nic Tob Res 2:19–37

    Article  CAS  Google Scholar 

  • Wetscher GJ, Bagchi M, Bagchi D, Perdikis G, Hinder PR, Glaser K, Hinder RA (1995) Free radical production in nicotine treated rats. Free Rad Biol Med 18:877–882

    Article  CAS  PubMed  Google Scholar 

  • Xia X, Ma Y, Xing X, Huang C, Li L, Gui G, Liu Q, Xue S (2013) Antioxidant and hepatoprotective effect of different extracts of guizhencao (herba bidentis bipinnatae) against liver injury in hyperlipidemia rats. J Tradit Chin Med 33:518–523

    Article  PubMed  Google Scholar 

  • Yildiz D, Liu YS, Ercal N, Armstrong DW (1999) Comparison of pure nicotine and smokeless tobacco extract induced toxicities and oxidative stress. Arch Environ Contam Toxicol 37:434–439

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ghalia M Attia.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

El-Sherbeeny, N.A., Nader, M.A., Attia, G.M. et al. Agmatine protects rat liver from nicotine-induced hepatic damage via antioxidative, antiapoptotic, and antifibrotic pathways. Naunyn-Schmiedeberg's Arch Pharmacol 389, 1341–1351 (2016). https://doi.org/10.1007/s00210-016-1284-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-016-1284-9

Keywords

Navigation