Skip to main content

Advertisement

Log in

Gastric Pentadecapeptide BPC 157 and Short Bowel Syndrome in Rats

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

The gastric pentadecapeptide BPC 157, which was shown to be safe as an antiulcer peptide in trials for inflammatory bowel disease (PL14736, Pliva), successfully healed intestinal anastomosis and fistula in rat. Therefore, we studied for 4 weeks rats with escalating short bowel syndrome and progressive weight loss after small bowel resection from fourth ileal artery cranially of ileocecal valve to 5 cm beneath pylorus. BPC 157 (10 μg/kg or 10 ng/kg) was given perorally, in drinking water (12 ml/rat/day) or intraperitoneally (once daily, first application 30 min following surgery, last 24 h before sacrifice). Postoperatively, features of increasingly exhausted presentation were: weight loss appearing immediately regardless of villus height, twofold increase in crypt depth and fourfold increase in muscle thickness within the first week, jejunal and ileal overdilation, and disturbed jejunum/ileum relation. In contrast, constant weight gain above preoperative values was observed immediately with BPC 157 therapy, both perorally and parenterally, and villus height, crypt depth, and muscle thickness [inner (circular) muscular layer] also increased, at 7, 14, 21, and 28 days. Moreover, rats treated with pentadecapeptide BPC 157 showed not different jejunal and ileal diameters, constant jejunum-to-ileum ratio, and increased anastomosis breaking strength. In conclusion, pentadecapeptide BPC 157 could be helpful to cure short bowel syndrome.

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

Similar content being viewed by others

References

  1. Vuksic T, Zoricic I, Brcic L, et al. Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, PL14736, Pliva, Croatia) heals ileoileal anastomosis in the rat. Surg Today. 2007;37:768–777.

    Article  PubMed  Google Scholar 

  2. Zoricic I, Sikiric P, Seiwerth S. Pentadecapeptide BPC 157 beneficially influences the healing of colon-colon anastomoses in rats. In: Mozsik G, Nagy L, Par A, Rainsford KD, eds. Cell injury and Protection in the Gastrointestinal Tract. From Basic Sciences to Clinical Perspectives 1996. Dodrecht, Boston, London: Kluwer Academic; 1997:249–258.

    Google Scholar 

  3. Pereira PM, Bines JE. New growth factor therapies aimed at improving intestinal adaptation in short bowel syndrome. J Gastroenterol Hepatol. 2006;21:932–940.

    Article  PubMed  Google Scholar 

  4. Sukhotnik I, Slijper N, Karry R, et al. Bombesin stimulates enterocyte turnover following massive small bowel resection in a rat. Pediatr Surg Int. 2007;23:397–404.

    Article  PubMed  Google Scholar 

  5. Vanderhoof JA, Kollman KA, Griffin S, Adrian TE. Growth hormone and glutamine do not stimulate intestinal adaptation following massive small bowel resection in the rat. J Pediatr Gastroenterol Nutr. 1997;25:327–331.

    Article  PubMed  Google Scholar 

  6. Zhou X, Li YX, Li N, Li JS. Effect of bowel rehabilitative therapy on structural adaptation of remnant small intestine: animal experiment. World J Gastroenterol. 2001;7:66–73.

    PubMed  Google Scholar 

  7. Osowska S, Moinard C, Neveux N, Loı C, Cynober L. Citrulline increases arginine pools and restores nitrogen balance after massive intestinal resection. Gut. 2004;53:1781–1786.

    Article  PubMed  Google Scholar 

  8. Eizaguirre I, Aldazabal P, Barrena MJ, et al. Effect of growth hormone, epidermal growth factor, and insulin on bacterial translocation in experimental short bowel syndrome. J Pediatr Surg. 2000;35:692–695.

    Article  PubMed  Google Scholar 

  9. Kato Y, Yu D, Schwartz MZ. Enhancement of intestinal adaptation by hepatocyte growth factor. J Pediatr Surg. 1998;33:235–239.

    Article  PubMed  Google Scholar 

  10. Fiore NF, Ledniczky G, Liu Q, et al. Comparison of interleukin-11 and epidermal growth factor on residual small intestine after massive small bowel resection. J Pediatr Surg. 1998;33:24–29.

    Article  PubMed  Google Scholar 

  11. Drucker DJ. Gut adaptation and the glucagon-like peptides. Gut. 2002;50:428–435.

    Article  PubMed  Google Scholar 

  12. Gillingham MB, Dahly EM, Murali SG, Ney DM. IGF-I treatment facilitates transition from parenteral to enteral nutrition in rats with short bowel syndrome. Am J Physiol Regul Integr Comp Physiol. 2003;284:R363–R371.

    PubMed  Google Scholar 

  13. Petersen TI, Kissmeyer-Nielsen P, Flyvbjerg A, Laurberg S, Christensen H. Effect of insulin-like growth factor I (IGF-I) administration on the healing of colonic anastomoses in rats. Int J Colorectal Dis. 1996;11:19–24.

    Article  PubMed  Google Scholar 

  14. Christensen H, Oxlund H, Laurberg S. Growth hormone increases the bursting strength of colonic anastomoses. An experimental study in the rat. Int J Colorectal Dis. 1990;5:130–134.

    Article  PubMed  Google Scholar 

  15. Seyer-Hansen M, Andreassen TT, Oxlund H. Strength of colonic anastomoses and skin incisional wounds in old rats - influence by diabetes and growth hormone. Growth Horm IGF Res. 1999;9:254–261.

    Article  PubMed  Google Scholar 

  16. Sigalet DL, Martin GR. Hormonal therapy for short bowel syndrome. J Pediatr Surg. 2000;35:360–364.

    Article  PubMed  Google Scholar 

  17. Sikiric P, Seiwerth S, Grabarevic Z, et al. The beneficial effect of BPC 157, a 15 aminoacid peptide BPC fragment, on gastric and duodenal lesion induced by restraint stress, cysteamine and 96% ethanol in rats. A comparative study with H2 receptor antagonists, dopamine promoters and gut peptides. Life Sci. 1994;54:PL63–PL68.

    Article  PubMed  Google Scholar 

  18. Sikiric P, Seiwerth S, Grabarevic Z, et al. The influence of a novel pentadecapeptide BPC 157 on NG-nitro-L-arginine methylester and L-arginine effect on stomach mucosal integrity and blood pressure. Eur J Pharmacol. 1997;332:23–33.

    Article  PubMed  Google Scholar 

  19. Sikiric P, Seiwerth S, Grabarevic Z, et al. Beneficial effect of novel pentadecapeptide BPC 157 on gastric lesions induced by restraint stress, ethanol, indomethacin, and capsaicin neurotoxicity. Dig Dis Sci. 1996;41:1604–1614.

    Article  PubMed  Google Scholar 

  20. Petrovic I, Dobric I, Drvis P, et al. An experimental model of prolonged esophagitis with sphincter failure in rat and therapeutic potential of gastric pentadecapeptide BPC 157. J Pharmacol Sci. 2006;102:269–277.

    Article  PubMed  Google Scholar 

  21. Dobric I, Drvis P, Petrovic I, et al. Prolonged esophagitis after primary dysfunction of the pyloric sphincter in the rat and therapeutic potential of the gastric pentadecapeptide BPC 157. J Pharmacol Sci. 2007;104:7–18.

    Article  PubMed  Google Scholar 

  22. Sikiric P, Mikus D, Seiwerth S, et al. Pentadecapeptide BPC 157, cimetidine, ranitidine, bromocriptine and atropine effect in cysteamine lesions in totally gastrectromized rats: a model for cytoprotective studies. Dig Dis Sci. 1997;42:1029–1037.

    Article  PubMed  Google Scholar 

  23. Sikiric P, Jadrijevic S, Seiwerth S, et al. Long-lasting cytoprotection after pentadecapeptide BPC 157, ranitidine, sucralfate or cholestyramine application in reflux oesophagitis in rats. J Physiol (Paris). 1999;93:467–477.

    Article  Google Scholar 

  24. Sikiric P, Seiwerth S, Deskovic S, et al. New model of cytoprotection/adaptive cytoprotection in rats: endogenous small irritants, antiulcer agents and indomethacin. Eur J Pharmacol. 1999;364:23–31.

    Article  PubMed  Google Scholar 

  25. Sikiric P, Seiwerth S, Grabarevic Z, et al. Cysteamine-colon and cysteamine-duodenum lesions in rats. Attenuation by gastric pentadecapeptide BPC 157, cimetidine, ranitidine, atropine, omeprazole, sulphasalazine and methylprednisolone. J Physiol (Paris). 2001;95:261–270.

    Google Scholar 

  26. Sikiric P, Seiwerth S, Aralica G, et al. Therapy effect of antiulcer agents on new chronic cysteamine colon lesion in rat. J Physiol (Paris). 2001;95:283–288.

    Article  Google Scholar 

  27. Xue XC, Wu YJ, Gao MT, Li WG, et al. Protective effects of pentadecapeptide BPC 157 on gastric ulcer in rats. World J Gastroenterol. 2004;10:1032–1036.

    PubMed  Google Scholar 

  28. Veljaca M, Lesch CA, Pllana R, Sanchez B, Chan K, Guglietta A. BPC–15 reduces trinitrobenzene sulfonic acid-induced colonic damage in rats. J Pharmacol Exp Ther. 1994;272:417–422.

    Google Scholar 

  29. Klicek R, Sever M, Radic B, et al. Pentadecapeptide BPC 157, in clinical trials as a therapy for inflammatory bowel disease (PL 14736, Pliva), is effective in the healing of colocutaneous fistulas in rats: the role of NO-system. J Pharm Sci. 2008;108:7–17.

    Google Scholar 

  30. Skorjanec S, Dolovski Z, Kocman I, et al. Therapy for unhealed gastrocutaneous fistulas in rats as a model for analogous healing of persistent skin wounds and persistent gastric ulcers: stable gastric pentadecapeptide BPC 157, atropine, ranitidine, and omeprazole. Dig Dis Sci. 2008 (in press).

  31. Seiwerth S, Sikiric P, Grabarevic Z, et al. BPC 157’s effect on healing. J Physiol (Paris). 1997;91:173–178.

    Article  Google Scholar 

  32. Mikus D, Sikiric P, Seiwerth S, et al. Pentadecapeptide BPC 157 cream improves burn-wound healing and attenuates burn-gastric lesions in mice. Burns. 2001;27:817–827.

    Article  PubMed  Google Scholar 

  33. Sikiric P, Seiwerth S, Mise S, et al. Corticosteroids-impairment healing and gastric pentadecapeptide BPC 157 creams in burned mice. Burns. 2003;29:323–334.

    PubMed  Google Scholar 

  34. Seveljevic Jaran D, Cuzic S, Dominis Kramaric M, et al. Accelerated healing of excisional skin wound by PL 14736 in alloxan-hyperglycemic rats. Skin Pharmacol Physiol. 2006;19:266–274.

    Article  PubMed  Google Scholar 

  35. Xue XC, Wu YJ, Gao MT. Study of the protective effects of pentadecapeptide BPC 157 on wounds in small type pigs. Chin New Drugs J. 2004;12:602–604.

    Google Scholar 

  36. Tkalcevic VI, Cuzic S, Brajsa K, et al. Enhancement by PL 14736 of granulation and collagen organization in healing wounds and the potential role of egr-1 expression. Eur J Pharmacol. 2007;570:212–221.

    Article  PubMed  Google Scholar 

  37. Bilic M, Bumber Z, Blagaic AB, Batelja L, Seiwerth S, Sikiric P. The stable gastric pentadecapeptide BPC 157, given locally, improves CO2 laser healing in mice. Burns. 2005;31:310–315.

    Article  PubMed  Google Scholar 

  38. Staresinic M, Petrovic I, Novinscak T, et al. Effective therapy of transected quadriceps muscle in rat: gastric pentadecapeptide BPC 157. J Orthop Res. 2006;24:1109–1117.

    Article  PubMed  Google Scholar 

  39. Novinscak T, Brcic L, Staresinic M, et al. Gastric pentadecapeptide BPC 157 as an effective therapy for muscle crush injury in the rat. Surg Today. 2008;38:716–725.

    Google Scholar 

  40. Staresinic M, Sebecic B, Jadrijevic S, et al. Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth. J Orthopaed Res. 2003;21:976–983.

    Article  Google Scholar 

  41. Sebecic B, Nikolic V, Sikiric P, et al. Osteogenic effect of a gastric pentadecapeptide BPC 157, on the healing of segmental bone defect in rabbits. A comparison with bone marrow and autologous cortical bone implantation. Bone. 1999;24:195–202.

    Article  PubMed  Google Scholar 

  42. Lazić R, Gabrić N, Dekaris I, Bosnar D, Boban-Blagaić A, Sikirić P. Gastric pentadecapeptide BPC 157 promotes corneal epithelial defects healing in rats. Coll Antropol. 2005;29:321–325.

    PubMed  Google Scholar 

  43. Krivic A, Anic T, Seiwerth S, Huljev D, Sikiric P. Achilles detachment in rat and stable gastric pentadecapeptide BPC 157: promoted tendon-to-bone healing and opposed corticosteroid aggravation. J Orthop Res. 2006;24:982–989.

    Article  PubMed  Google Scholar 

  44. Veljaca M, Pavic Sladoljev D, Mildner B, et al. Safety, tolerability and pharmacokinetics of PL 14736, a novel agent for treatment of ulcerative colitis, in healthy male volunteers. Gut. 2003;51 (Suppl III):A309.

    Google Scholar 

  45. Ruenzi M, Stolte M, Veljaca M, Oreskovic K, Peterson J, Ulcerative Colitis Study Group. A multicenter, randomized, double blind, placebo-controlled phase II study of PL 14736 enema in the treatment of mild-to-moderate ulcerative colitis. Gastroenterology. 2005;128:A584.

    Google Scholar 

  46. Urist MR. The first three decades of bone morphogenetic protein. Osteologie. 1996;4:207–233.

    Google Scholar 

  47. Mustoe TA, Pierce GF, Thomason A, Gramates P, Sporn MB, Duel TF. Accelerated healing of incisional wounds in rats induced by transforming growth factor-β. Science. 1987;237:1333–1336.

    Article  PubMed  Google Scholar 

  48. Veljaca M, Chan K, Guglietta A. Digestion of h-EGF, h-TGF alpha and BPC–15 in human gastric juice. Gastroenterology. 1995;108:A761.

    Google Scholar 

  49. Mise S, Tonkic A, Pesutic V, et al. The presentation and organization of adaptive cytoprotection in the rat stomach, duodenum, and colon. Dedicated to Andre Robert the founder of the concept of cytoprotection and adaptive cytoprotection. Med Sci Monit. 2006;12:BR146–153.

    Google Scholar 

  50. Prkacin I, Aralica G, Perovic D, et al. Chronic cytoprotection: pentadecapeptide BPC 157, ranitidine and propranolol prevent, attenuate and reverse the gastric lesions appearance in chronic alcohol drinking rats. J Physiol (Paris). 2001;95:295–301.

    Article  Google Scholar 

  51. Sikiric P, Petek M, Rucman R, et al. A new gastric peptide BPC. An overview of stomach – organoprotection hypothesis and beneficial effect of BPC. J Physiol (Paris). 1993;87:313–327.

    Google Scholar 

  52. Wood JD. The first Nobel prize for integrated systems physiology: Ivan Petrovich Pavlov, 1904. Physiology. 2004;19:326–330.

    Article  PubMed  Google Scholar 

  53. Sikiric P, Seiwerth S, Brcic L, et al. Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL–10, PLD–116, Pliva, Croatia). Full and distended stomach, and vascular response. Inflammopharmacology. 2006;14:1–8.

    Article  Google Scholar 

  54. Lovric-Bencic M, Sikiric P, Separovic J, et al. Doxorubicine congestive heart failure-increased big-endothelin 1 plasma concentration: reversal by amlodipine, losartan and gastric pentadecapeptide BPC 157 in rat and mouse. J Pharmacol Sci. 2004;95:19–26.

    Article  PubMed  Google Scholar 

  55. Sikiric P, Separovic J, Anic T, et al. The effect of pentadecapeptide BPC 157, H2-blockers, omeprazole and sucralfate on new vessels and new granulation tissue formation. J Physiol (Paris). 1999;93:479–485.

    Google Scholar 

  56. Radeljak S, Seiwerth S, Sikiric P. BPC 157 inhibits cell growth and VEGF signalling via the MAPK kinase pathway in the human melanoma cell line. Melanoma Res. 2004;14:A14–A15.

    Article  Google Scholar 

  57. Mozsik G, Sikiric P, Seiwerth S. Pentadecapeptide BPC 157 (PLD116, PL14736, Pliva) influences ATP energy system and antagonizes 0.6M HCl- and 96% ethanol-gastric lesion in rat. Digestion. 2005;73:41.

  58. Pawlik WW, Sikiric P, Brzozowski T, et al. Acceleration of ulcer healing by pentadecapeptide BPC 157 in rats. Involvement of endogenous prostaglandinsand gastric secretion. Gastroenterology. 2004;126:A541.

    Google Scholar 

  59. Sikiric P, Seiwerth S, Grabarevic Z, et al. Pentadecapeptide BPC 157 positively affects both non-steroidal anti-inflammagtory agent-induced gastrointestinal lesions and adjuvant arthritis in rats. J Physiol (Paris). 1997;91:113–122.

    Article  Google Scholar 

  60. Turkovic B, Sikiric P, Seiwerth S, et al. Stable gastric pentadecapeptide BPC 157 studied for inflammatory bowel disease (PLD–116, PL14736, Pliva) induces nitric oxide synthesis. Gastroenterology. 2004;126:287.

    Google Scholar 

  61. Krivic A, Majerovic M, Jelic I, Seiwerth S, Sikiric P. Modulation of early functional recovery of Achilles tendon to bone unit after transection by BPC 157 and methylprednisolone. Inflamm Res. 2008;57:205–210.

    Article  PubMed  Google Scholar 

  62. Sandor Z, Vincze A, Jadus MR, Brajsa K, Kolega M, Szabo S. The protective effect of newly isolated peptide PL-10 in the iodoacetamide colitis in rats. Gastroenterology. 1997;112:400.

    Google Scholar 

  63. Hastings JC, Winkle WV Jr, Barker E, Hines D, Nichols W. Effect of suture materials on healing wounds of the stomach and colon. Surg Gynecol Obstet. 1975;140:701–770.

    PubMed  Google Scholar 

  64. Frank S, Madlener M, Pfeilschifter J, Werner S. Induction of inducible nitric oxide synthase and its corresponding tetrahydrobiopterin-cofactor-synthesizing enzyme GTP-cyclohydrolase I during cutaneous wound repair. J Invest Dermatol. 1998;111:1058–1064.

    Article  PubMed  Google Scholar 

  65. Attard JA, Raval MJ, Martin GR, et al. The effects of systemic hypoxia on colon anastomotic healing: an animal model, Dis Colon Rectum. 2005;48 : 1460–1470.

    Google Scholar 

  66. Ulland AE, Shearer JD, Coulter C, Caldwell MD. Altered wound arginine metabolism by corticosterone and retinoic acid. J Surg Res. 1997;70:84–88.

    Google Scholar 

  67. Camli A, Barlas M, Yagmurlu A. Does L-arginine induce intestinal adaptation by epithelial growth factor? ANZ J Surg. 2005;75:73–75.

    Article  PubMed  Google Scholar 

  68. Kato S, Pinto M, Carvajal A, et al. Tissue factor is regulated by epidermal growth factor in normal and malignant human endometrial epithelial cells. Thromb Haemost. 2005;94:444–453.

    PubMed  Google Scholar 

  69. Festuccia C, Angelucci A, Gravina GL, et al. Epidermal growth factor modulates prostate cancer cell invasiveness regulating urokinase-type plasminogen activator activity. EGF-receptor inhibition may prevent tumor cell dissemination. Thromb Haemost. 2005;93:964–975.

    PubMed  Google Scholar 

  70. Boban Blagaic A, Mirt Dabic M, Blagaic V, Sikiric P. Pentadecapeptide BPC 157 anagonizes rat ethanol gastric lesion and influences VEGF mRNA. Eur J Biochem. 2003;271:247.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Predrag Sikiric.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sever, M., Klicek, R., Radic, B. et al. Gastric Pentadecapeptide BPC 157 and Short Bowel Syndrome in Rats. Dig Dis Sci 54, 2070–2083 (2009). https://doi.org/10.1007/s10620-008-0598-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-008-0598-y

Keywords

Navigation