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Inflammopharmacology

, Volume 25, Issue 2, pp 255–264 | Cite as

Cyclophosphamide induced stomach and duodenal lesions as a NO-system disturbance in rats: l-NAME, l-arginine, stable gastric pentadecapeptide BPC 157

  • Krešimir Luetic
  • Mario Sucic
  • Josipa Vlainic
  • Zeljka Belosic Halle
  • Dean Strinic
  • Tinka Vidovic
  • Franka Luetic
  • Marinko Marusic
  • Sasa Gulic
  • Tatjana Turudic Pavelic
  • Antonio Kokot
  • Ranka Serventi Seiwerth
  • Domagoj Drmic
  • Lovorka Batelja
  • Sven Seiwerth
  • Predrag SikiricEmail author
Original Article

Abstract

We revealed a new point with cyclophosphamide (150 mg/kg/day intraperitoneally for 7 days): we counteracted both rat stomach and duodenal ulcers and increased NO- and MDA-levels in these tissues. As a NO-system effect, BPC 157 therapy (10 µg/kg, 10 ng/kg, intraperitoneally once a day or in drinking water, till the sacrifice) attenuated the increased NO- and MDA-levels and nullified, in rats, severe cyclophosphamide-ulcers and even stronger stomach and duodenal lesions after cyclophosphamide + l-NAME (5 mg/kg intraperitoneally once a day). l-arginine (100 mg/kg intraperitoneally once a day not effective alone) led l-NAME-values only to the control values (cyclophosphamide + l-NAME + l-arginine-rats). Briefly, rats were sacrificed at 24 h after last administration on days 1, 2, 3, or 7, and assessment included sum of longest lesions diameters (mm) in the stomach and duodenum, oxidative stress by quantifying thiobarbituric acid reactivity as malondialdehyde equivalents (MDA), NO in stomach and duodenal tissue samples using the Griess reaction. All these parameters were highly exaggerated in rats who underwent cyclophosphamide treatment. We identified high MDA-tissue values, high NO-tissue values, ulcerogenic and beneficial potential in cyclophosphamide-l-NAME-l-arginine-BPC 157 relationships. This suggests that in cyclophosphamide damaged rats, NO excessive release generated by the inducible isozyme, damages the vascular wall and other tissue cells, especially in combination with reactive oxygen intermediates, while failing endothelial production and resulting in further aggravation by l-NAME which was inhibited by l-arginine. Finally, BPC 157, due to its special relations with NO-system, may both lessen increased MDA- and NO-tissues values and counteract effects of both cyclophosphamide and l-NAME on stomach and duodenal lesions.

Keywords

BPC 157 Cyclophosphamide Duodenal lesions Gastric lesions NO-system NO-MDA-tissue levels Rats 

Notes

Acknowledgements

This research was supported from Ministry of Science, Education and Sports, Republic of Croatia (Grant Number 108-1083570-3635).

Compliance with ethical standards

Conflict of interest

The authors indicated no potential conflicts of interest.

References

  1. Al-Yahya AA, Al-Majed AA, Gado AM, Daba MH, Al-Shabanah OA, Abd-Allah AR (2009) Acacia Senegal gum exudate offers protection against cyclophosphamide-induced urinary bladder cytotoxicity. Oxid Med Cell Longev 2:207–213CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bakan E, Taysi S, Polat MF, Dalga S, Umudum Z, Bakan N, Gumus M (2002) Nitric oxide levels and lipid peroxidation in plasma of patients with gastric cancer. Jpn J Clin Oncol 32:162–166CrossRefPubMedGoogle Scholar
  3. Barisic I, Balenovic D, Klicek R et al (2013) Mortal hyperkalemia disturbances in rats are NO-system related. The life saving effect of pentadecapeptide BPC 157. Regul Pept 181:50–66CrossRefPubMedGoogle Scholar
  4. Bedekovic V, Mise S, Anic T et al (2003) Different effect of antiulcer agents on rat cysteamine-induced duodenal ulcer after sialoadenectomy, but not gastrectomy. Eur J Pharmacol 477:73–80CrossRefPubMedGoogle Scholar
  5. Beevi SS, Rasheed AM, Geetha A (2004) Evaluation of oxidative stress and nitric oxide levels in patients with oral cavity cancer. Jpn J Clin Oncol 34:379–385CrossRefPubMedGoogle Scholar
  6. Bilic I, Zoricic I, Anic T et al (2001) Haloperidol-stomach lesions attenuation by pentadecapeptide BPC 157, omeprazole, bromocriptine, but not atropine, lansoprazole, pantoprazole, ranitidine, cimetidine and misoprostol in mice. Life Sci 68(16):1905–1912CrossRefPubMedGoogle Scholar
  7. Blagaic AB, Blagaic V, Romic Z, Sikiric P (2004) The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice. Eur J Pharmacol 499:285–290CrossRefPubMedGoogle Scholar
  8. Boban-Blagaic A, Blagaic V, Romic Z et al (2006) The influence of gastric pentadecapeptide BPC 157 on acute and chronic ethanol administration in mice. The effect of N(G)-nitro-l-arginine methyl ester and l-arginine. Med Sci Monit 12:BR36–45PubMedGoogle Scholar
  9. Boddy AV, Yule SM (2000) Metabolism and pharmacokinetics of oxazaphosphorines. Clin Pharmacokinet 38:291–304CrossRefPubMedGoogle Scholar
  10. Brcic L, Brcic I, Staresinic M, Novinscak T, Sikiric P, Seiwerth S (2009) Modulatory effect of gastric pentadecapeptide BPC 157 on angiogenesis in muscle and tendon healing. J Physiol Pharmacol 60(Suppl 7):191–196PubMedGoogle Scholar
  11. Cesarec V, Becejac T, Misic M et al (2013) Pentadecapeptide BPC 157 and the esophagocutaneous fistula healing therapy. Eur J Pharmacol 701:203–212CrossRefPubMedGoogle Scholar
  12. Chang CH, Tsai WC, Lin MS, Hsu YH Pang JH (2011) The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration. J Appl Physiol 110:774–780CrossRefPubMedGoogle Scholar
  13. Chang CH, Tsai WC, Hsu YH, Pang JH (2014) Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules 19:19066–19077CrossRefPubMedGoogle Scholar
  14. Dincer Y, Akcay T, Tortum OB, Dogusoy G (2006) Nitric oxide and antioxidant defense in patients with gastric cancer. Dig Dis Sci 51:1367–1370CrossRefPubMedGoogle Scholar
  15. Hsieh MJ, Liu HT, Wang CN et al. (2017) Therapeutic potential of pro-angiogenic BPC157 is associated with VEGFR2 activation and up-regulation. J Mol Med (Berl) 95:323–333CrossRefGoogle Scholar
  16. Huang T, Zhang K, Sun L et al (2015) Body protective compound-157 enhances alkali-burn wound healing in vivo and promotes proliferation, migration, and angiogenesis in vitro. Drug Des Devel Ther 9:2485–2499CrossRefPubMedPubMedCentralGoogle Scholar
  17. Ilic S, Drmic D, Zarkovic K et al (2010) High hepatotoxic dose of paracetamol produces generalized convulsions and brain damage in rats. A counteraction with the stable gastric pentadecapeptide BPC 157 (PL 14736). J Physiol Pharmacol 61:241–250PubMedGoogle Scholar
  18. Ilic S, Drmic D, Franjic S et al (2011a) Pentadecapeptide BPC 157 and its effects on a NSAID toxicity model: diclofenac-induced gastrointestinal, liver, and encephalopathy lesions. Life Sci 88:535–542CrossRefPubMedGoogle Scholar
  19. Ilic S, Drmic D, Zarkovic K et al (2011b) Ibuprofen hepatic encephalopathy, hepatomegaly, gastric lesion and gastric pentadecapeptide BPC 157 in rats. Eur J Pharmacol 667:322–329CrossRefPubMedGoogle Scholar
  20. Kokot A, Zlatar M, Stupnisek M et al (2016) NO system dependence of atropine-induced mydriasis and l-NAME- and l-arginine-induced miosis: reversal by the pentadecapeptide BPC 157 in rats and guinea pigs. Eur J Pharmacol 771:211–219CrossRefPubMedGoogle Scholar
  21. Mansour HH, El Kiki SM, Hasan HF (2015) Protective effect of N-acetylcysteine on cyclophosphamide-induced cardiotoxicity in rats. Environ Toxicol Pharmacol 40(2):417–422CrossRefPubMedGoogle Scholar
  22. Marchitti SA, Brocker C, Stagos D, Vasiliou V (2008) Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily. Expert opinion on drug metabolism and toxicology 4:697–720CrossRefPubMedPubMedCentralGoogle Scholar
  23. Matthys KE, Bult H (1997) Nitric oxide function in atherosclerosis. Mediators Inflamm 6:3–21CrossRefPubMedPubMedCentralGoogle Scholar
  24. Moncada S, Palmer RMJ, Higgs EA (1991) Nitric oxide: physiology and pharmacology. Pharmacol Rev 43:109–142PubMedGoogle Scholar
  25. Ozawa H, Chancellor MB, Jung SY et al (1999) Effect of intravesical nitric oxide therapy on cyclophosphamide-induced cystitis. J Urol 162:2211–2216CrossRefPubMedGoogle Scholar
  26. Prkacin I, Separovic J, Aralicia G et al (2001a) Portal hypertension and liver lesions in chronically alcohol drinking rats prevented and reversed by stable gastric pentadecapeptide BPC 157 (PL-10, PLD-116), and propranolol, but not ranitidine. J Physiol Paris 95:315–324CrossRefPubMedGoogle Scholar
  27. Prkacin I, Aralica G, Perovic D et al (2001b) Chronic cytoprotection: pentadecapeptide BPC 157, ranitidine and propranolol prevent, attenuate and reverse the gastric lesions appearance in chronic alcohol drinking rats. J Physiol Paris 95:295–301CrossRefPubMedGoogle Scholar
  28. Ribeiro RA, Freitas HC, Campos MC et al (2002) Tumor necrosis factor-alpha and interleukin-1beta mediate the production of nitric oxide involved in the pathogenesis of ifosfamide induced hemorrhagic cystitis in mice. J Urol 167:2229–2234CrossRefPubMedGoogle Scholar
  29. Sartori S, Trevisani L, Nielsen I, Tassinari D, Panzini I, Abbasciano V (2000) Randomized trial of omeprazole or ranitidine versus placebo in the prevention of chemotherapy-induced gastroduodenal injury. J Clin Oncol 18:463–467CrossRefPubMedGoogle Scholar
  30. Seiwerth S, Brcic L, Vuletic LB et al (2014) BPC 157 and blood vessels. Curr Pharm Des 20:1121–1125CrossRefPubMedGoogle Scholar
  31. Seven A, Civelek S, Inci E, Inci F, Korkut N, Burçak G (1999) Evaluation of oxidative stress parameters in blood of patients with laryngeal carcinoma. Clin Biochem 32:369–373CrossRefPubMedGoogle Scholar
  32. Sikiric P, Seiwerth S, Grabarevic Z et al (1993) Hepatoprotective effect of BPC 157, a 15-amino acid peptide, on liver lesions induced by either restraint stress or bile duct and hepatic artery ligation or CCl4 administration. A comparative study with dopamine agonists and somatostatin. Life Sci 53:PL291–296CrossRefPubMedGoogle Scholar
  33. Sikiric P, Seiwerth S, Grabarevic Z et al (1994) The beneficial effect of BPC 157, a 15 amino acid peptide BPC fragment, on gastric and duodenal lesions induced by restraint stress, cysteamine and 96% ethanol in rats. A comparative study with H2 receptor antagonists, dopamine promotors and gut peptides. Life Sci 54(5):PL63–68CrossRefPubMedGoogle Scholar
  34. Sikiric P, Seiwerth S, Grabarevic Z et al (1996a) Beneficial effect of a novel pentadecapeptide BPC 157 on gastric lesions induced by restraint stress, ethanol, indomethacin, and capsaicin neurotoxicity. Dig Dis Sci 41:1604–1614CrossRefPubMedGoogle Scholar
  35. Sikiric P, Seiwerth S, Grabarevic Z et al (1996b) Salutary and prophylactic effect of pentadecapeptide BPC 157 on acute pancreatitis and concomitant gastroduodenal lesions in rats. Dig Dis Sci 41:1518–1526CrossRefPubMedGoogle Scholar
  36. Sikiric P, Seiwerth S, Grabarevic Z et al (1997) The influence of a novel pentadecapeptide, BPC 157, on N(G)-nitro-l-arginine methylester and l-arginine effects on stomach mucosa integrity and blood pressure. Eur J Pharmacol 332:23–33CrossRefPubMedGoogle Scholar
  37. Sikiric P, Seiwerth S, Deskovic S et al (1999a) New model of cytoprotection/adaptive cytoprotection in rats: endogenous small irritants, antiulcer agents and indomethacin. Eur J Pharmacol 364:23–31CrossRefPubMedGoogle Scholar
  38. Sikiric P, Separovic J, Anic T et al (1999b) The effect of pentadecapeptide BPC 157, H2-blockers, omeprazole and sucralfate on new vessels and new granulation tissue formation. J Physiol Paris 93:479–485CrossRefPubMedGoogle Scholar
  39. Sikiric P, Seiwerth S, Grabarevic Z et al (2001) Cysteamine-colon and cysteamine-duodenum lesions in rats. Attenuation by gastric pentadecapeptide BPC 157, cimetidine, ranitidine, atropine, omeprazole, sulphasalazine and methylprednisolone. J Physiol Paris 95:261–270CrossRefPubMedGoogle Scholar
  40. Sikiric P, Seiwerth S, Brcic L et al (2006) Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, PL 14736, Pliva, Croatia). Full and distended stomach, and vascular response. Inflammopharmacology 14:214–221CrossRefPubMedGoogle Scholar
  41. Sikiric P, Seiwerth S, Brcic L et al (2010) Revised Robert’s cytoprotection and adaptive cytoprotection and stable gastric pentadecapeptide BPC 157. Possible significance and implications for novel mediator. Curr Pharm Des 16:1224–1234CrossRefPubMedGoogle Scholar
  42. Sikiric P, Seiwerth S, Rucman R et al (2011) Stable gastric pentadecapeptide BPC 157: novel therapy in gastrointestinal tract. Curr Pharm Des 17:1612–1632CrossRefPubMedGoogle Scholar
  43. Sikiric P, Seiwerth S, Rucman R et al (2012) Focus on ulcerative colitis: stable gastric pentadecapeptide BPC 157. Curr Med Chem 19:126–132CrossRefPubMedGoogle Scholar
  44. Sikiric P, Seiwerth S, Rucman R et al (2013) Toxicity by NSAIDs. Counteraction by stable gastric pentadecapeptide BPC 157. Curr Pharm Des 19:76–83PubMedGoogle Scholar
  45. Sikiric P, Seiwerth S, Rucman R et al (2014) Stable gastric pentadecapeptide BPC 157-NO-system relation. Curr Pharm Des 20:1126–1135CrossRefPubMedGoogle Scholar
  46. Sikirić P, Petek M, Rucman R et al (1993) A new gastric juice peptide, BPC. An overview of the stomach-stress-organoprotection hypothesis and beneficial effects of BPC. J Physiol Paris 87:313–327CrossRefPubMedGoogle Scholar
  47. Souza-Filho MV, Lima MV, Pompeu MM, Ballejo G, Cunha FQ, Ribeiro RA (1997) Involvement of nitric oxide in the pathogenesis of cyclophosphamide-induced hemorrhagic cystitis. Am J Pathol 150:247–256Google Scholar
  48. Stupnisek M, Franjic S, Drmic D et al (2012) Pentadecapeptide BPC 157 reduces bleeding time and thrombocytopenia after amputation in rats treated with heparin, warfarin or aspirin. Thromb Res 129:652–659CrossRefPubMedGoogle Scholar
  49. Stupnisek M, Kokot A, Drmic D et al (2015) Pentadecapeptide BPC 157 reduces bleeding and thrombocytopenia after amputation in rats treated with heparin, warfarin, l-NAME and l-arginine. PLoS One 10:e0123454CrossRefPubMedPubMedCentralGoogle Scholar
  50. Taysi S, Uslu C, Akcay F, Sutbeyaz MY (2003) Malondialdehyde and nitric oxide levels in the plasma of patients with advanced laryngeal cancer. Surg Today 33:651–654CrossRefPubMedGoogle Scholar
  51. Tkalcević VI, Cuzić S, Brajsa K et al (2007) Enhancement by PL 14736 of granulation and collagen organization in healing wounds and the potential role of egr-1 expression. Eur J Pharmacol 570:212–221CrossRefPubMedGoogle Scholar
  52. Tsakadze NL, Srivastava S, Awe SO, Adeagbo AS, Bhatnagar A, D’Souza SE (2003) Acrolein-induced vasomotor responses of rat aorta. Am J Physiol Heart Circ Physiol 285:H727–H734CrossRefPubMedGoogle Scholar
  53. Unsal D, Akmansu M, Ozer C, Gonul B, Bora H (2005) Plasma level of lipid peroxidation, total sulphydryl groups and nitric oxide levels in cancer patients irradiated on different anatomic fields: a case-control study. Exp Oncol 27:76–80PubMedGoogle Scholar
  54. Whittle BJR, Boughton-Smith NK, Moncada S (1992) Biosynthesis and role of the endothelium-derived vasodilator, nitric oxide in gastric mucosa. Ann NY Acad Sci 664:126–139CrossRefPubMedGoogle Scholar
  55. Xu X, Cubeddu LX, Malave A (2001) Expression of inducible nitric oxide synthase in primary culture of rat bladder smooth muscle cells by plasma from cyclophosphamide-treated rats. Eur J Pharmacol 416:1–9CrossRefPubMedGoogle Scholar
  56. Yousefipour Z, Ranganna K, Newaz MA, Milton SG (2005) Mechanism of acrolein-induced vascular toxicity. J Physiol Pharmacol 56:337–353PubMedGoogle Scholar

Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  • Krešimir Luetic
    • 1
    • 2
  • Mario Sucic
    • 1
    • 2
  • Josipa Vlainic
    • 1
  • Zeljka Belosic Halle
    • 1
    • 2
  • Dean Strinic
    • 1
    • 2
  • Tinka Vidovic
    • 1
  • Franka Luetic
    • 1
  • Marinko Marusic
    • 1
    • 2
  • Sasa Gulic
    • 1
  • Tatjana Turudic Pavelic
    • 1
  • Antonio Kokot
    • 1
    • 2
  • Ranka Serventi Seiwerth
    • 1
  • Domagoj Drmic
    • 1
  • Lovorka Batelja
    • 1
  • Sven Seiwerth
    • 1
  • Predrag Sikiric
    • 1
    Email author
  1. 1.Departments of Pharmacology and Pathology, School of MedicineUniversity of ZagrebZagrebCroatia
  2. 2.Faculty of MedicineJ.J. Strossmayer University of OsijekOsijekCroatia

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