Surgery Today

, Volume 38, Issue 8, pp 716–725 | Cite as

Gastric pentadecapeptide BPC 157 as an effective therapy for muscle crush injury in the rat

  • Tomislav Novinscak
  • Luka Brcic
  • Mario Staresinic
  • Ivana Jukic
  • Bozo Radic
  • Danira Pevec
  • Sandro Mise
  • Sanja Tomasovic
  • Iva Brcic
  • Tihomir Banic
  • Ana Jakir
  • Gojko Buljat
  • Tomislav Anic
  • Ivan Zoricic
  • Zeljko Romic
  • Sven Seiwerth
  • Predrag Sikiric
Original Articles

Abstract

Purpose

Stable gastric pentadecapeptide BPC 157 accelerates the healing of a transected Achilles tendon and a transected quadriceps muscle. It may also be of clinical relevance as a systemic and local peptide treatment for crush injury of a major muscle, such as gastrocnemius muscle complex. BPC 157 is effective without a carrier, and it is presently undergoing trials for inflammatory bowel disease, and no toxicity has so far been reported.

Methods

In crushed rats (force delivered 0.727 Ns/cm2), BPC 157 was applied either intraperitoneally or locally, as a thin cream layer, immediately after injury (sacrifice at 2 h), and once a day for 14 days.

Results

BPC 157 improved muscle healing, macroscopically (less hematoma and edema, no post-injury leg contracture), microscopically, functionally, and also based on enzyme activity (creatine kinase, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase).

Conclusion

BPC 157, at all investigated intervals, given locally or intraperitoneally, accelerated post-injury muscle healing and also helped to restore the full function.

Key words

BPC 157 Crush injury Peptide therapy Muscle regeneration Rat 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Sikiric P, Petek M, Rucman R, Seiwerth S, Grabarevic Z, Rotkvic I, 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.CrossRefGoogle Scholar
  2. 2.
    Sikiric P, Seiwerth S, Brcic L, Blagaic AB, Zoricic I, Sever M, et al. 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 2006;14:214–221.PubMedCrossRefGoogle Scholar
  3. 3.
    Wood JD. The first Nobel prize for integrated systems physiology: Ivan Petrovich Pavlov, 1904. Physiology 2004;19:326–330.PubMedCrossRefGoogle Scholar
  4. 4.
    Jelovac N, Sikiric P, Rucman R, Petek M, Marovic A, Perovic D, et al. Pentadecapeptide BPC 157 attenuates disturbances induced by neuroleptics: the effect on catalepsy and gastric ulcers in mice and rats. Eur J Pharmacol 1999;379:19–31.PubMedCrossRefGoogle Scholar
  5. 5.
    Sikiric P, Seiwerth S, Grabarevic Z, Rucman R, Petek M, Jagic V, et al. Beneficial effect of a novel pentadecapeptide BPC 157 on gastric lesions induced by restraint stress, ethanol, indomethacin, and capsaicin neurotoxicity. Dig Dis Sci 1996;41:1604–1614.PubMedCrossRefGoogle Scholar
  6. 6.
    Sikiric P, Seiwerth S, Grabarevic Z, Rucman R, Petek M, Jagic V, et al. 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 1997;332:23–33.PubMedCrossRefGoogle Scholar
  7. 7.
    Sikiric P, Seiwerth S, Mise S, Staresinic M, Bedekovic V, Zarkovic N, et al. Corticosteroid-impairment of healing and gastric pentadecapeptide BPC-157 creams in burned mice. Burns 2003;29:323–334.PubMedGoogle Scholar
  8. 8.
    Veljaca M, Chan K, Guglietta A. Digestion of h-EGF, h-TGF alpha, and BPC-15 in human gastric juice. Gastroenterology 1995;108:761.CrossRefGoogle Scholar
  9. 9.
    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;128:584.Google Scholar
  10. 10.
    Veljaca M, Krnic Z, Brajsa K, Mildner B, Pavic-Saladojev D, Seveljevic-Jaran D, et al. The development of PL 14736 for treatment of inflammatory bowel disease. IUPHAR-GI Section Symposium, Honolulu, Hawaii, 13–15 July, 2002. O–32.Google Scholar
  11. 11.
    Veljaca M, Pavic Sladoljev D, Mildner B, Brajsa K, Bubenik M, Stipanicic S, et al. Safety, tolerability and pharmacokinetics of PL 14736, a novel agent for treatment of ulcerative colitis, in healthy male volunteers. Gut 2003;51:A309.Google Scholar
  12. 12.
    Staresinic M, Petrovic I, Novinscak T, Jukic I, Pevec D, Suknaic S, et al. Effective therapy of transected quadriceps muscle in rat: Gastric pentadecapeptide BPC 157. J Orthop Res 2006;24:1109–1117.PubMedCrossRefGoogle Scholar
  13. 13.
    Krivic A, Sikiric P. Comment on “Use of recombinant human bone morphogenetic protein-2 to enhance tendon healing in a bone tunnel”. Am J Sports Med 2003;31:636–637.PubMedGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    Staresinic M, Sebecic B, Patrlj L, Jadrijevic S, Suknaic S, Perovic D, et al. Gastric pentadecapeptide BPC 157 accelerates healing of transected rat Achilles tendon and in vitro stimulates tendocytes growth. J Orthop Res 2003;21:976–983.PubMedCrossRefGoogle Scholar
  16. 16.
    Sebecic B, Nikolic V, Sikiric P, Seiwerth S, Sosa T, Patrlj L, 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.PubMedCrossRefGoogle Scholar
  17. 17.
    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.PubMedCrossRefGoogle Scholar
  18. 18.
    Mikus D, Sikiric P, Seiwerth S, Petricevic A, Aralica G, Druzijanic N, et al. Pentadecapeptide BPC 157 cream improves burn-wound healing and attenuates burn-gastric lesions in mice. Burns 2001;127:817–827.CrossRefGoogle Scholar
  19. 19.
    Seiwerth S, Sikiric P, Grabarevic Z, Zoricic I, Hanzevacki M, Ljubanovic D, et al. BPC 157’s effect on healing. J Physiol (Paris) 1997;91:173–178.CrossRefGoogle Scholar
  20. 20.
    Seveljevic Jaran D, Cuzic S, Dominis Kramaric M, Glojnaric I, Ivetic V, Radosevic S, et al. Accelerated healing of excisional skin wound by PL 14736 in alloxan-hyperglycemic rats. Skin Pharmacol Physiol 2006;19:266–274.PubMedCrossRefGoogle Scholar
  21. 21.
    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
  22. 22.
    Ivetic Tkalcevic I, Cuzic S, Brajsa K, Mildner B, Bokulic A, Situm 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.CrossRefGoogle Scholar
  23. 23.
    Gjurasin M, Miklic P, Buljat G, Perovic D, Jukic I, Sikiric P, et al. Selective healing effect of the gastric pentadecapeptide BPC 157 on injured part of the nerve in subtotal sciatic nerve transection. Dig Dis Sci 2003;48:1878.Google Scholar
  24. 24.
    Vuksic T, Zoricic I, Brcic L, Sever M, Klicek R, Radic B, et al. Stable gastric pentadecapeptide BPC 157 in trials for inflammatory bowel disease (PL-10, PLD-116, Pliva, Croatia) heals ileoileal-anastomosis in rat. Surg Today 2007;37:768–777.PubMedCrossRefGoogle Scholar
  25. 25.
    Järvinen TAH, Järvinen TLN, Minna Kääriäinen M, Kalimo H, Järvinen M. Muscle injuries: biology and treatment. Am J Sports Med 2005;33:745–762.PubMedCrossRefGoogle Scholar
  26. 26.
    Mustoe TA, Pierce GF, Thomason A, Gramates P, Sporn MB, Duel TF. Accelarated healing of incisional wounds in rats induced by transforming growth factor-β. Science 1987;237:1333–1336.PubMedCrossRefGoogle Scholar
  27. 27.
    Kurtz CA, Loebing TG, Anderson DD, DeMeo PJ, Campbell PG. Insulin-like growth factor I accelerates functional recovery from Achilles tendon injury in a rat model. Am J Sports Med 1999;27:363–369.PubMedGoogle Scholar
  28. 28.
    Urist MR. The first three decades of bone morphogenetic protein. Osteologie 1996;4:207–233.Google Scholar
  29. 29.
    Rubinestein I, Abassi Z, Coleman R, Milman F, Winaver J, Better OS. Involvement of nitric oxide system in experimental muscle crush injury. J Clin Invest 1998;101:1325–13333.CrossRefGoogle Scholar
  30. 30.
    Menetrey J, Kasemkijwattana C, Day CS, Bosch P, Vogt M, Fu FH, et al. Growth factors improve muscle healing in vivo. J Bone Joint Surg Br 2000;82:131–137.PubMedCrossRefGoogle Scholar
  31. 31.
    Fukushima K, Badlani N, Usas A, Riano F, Fu F, Huard J. The use of an antifibrosis agent to improve muscle recovery after laceration. Am J Sports Med 2001;29:394–402.PubMedGoogle Scholar
  32. 32.
    Crisco JJ, Jokl P, Heinen GT, Connell MD, Panjabi MM. A muscle contusion injury model. Biomechanics, physiology, and histology. Am J Sports Med 1994;22:702–710.PubMedCrossRefGoogle Scholar
  33. 33.
    Farges MC, Balcerzak D, Fisher BD, Attaix D, Bechet D, Ferrara M, et al. Increased muscle proteolysis after local trauma mainly reflects macrophage-associated lysosomal proteolysis. Am J Physiol Endocrinol Metab 2002;282:E326–E335.PubMedGoogle Scholar
  34. 34.
    Lovric-Bencic M, Sikiric P, Hanzevacki JS, Seiwerth S, Rogic D, Kusec V, 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.PubMedCrossRefGoogle Scholar
  35. 35.
    Prkacin I, Separovic J, Aralica G, Perovic D, Gjurasin M, Lovric-Bencic M, et al. 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) 2001;95:315–324.CrossRefGoogle Scholar
  36. 36.
    Rockey DC, Chung JJ. Endothelin antagonism in experimental hepatic fibrosis. Implications for endothelin in the pathogenesis of wound healing. J Clin Invest 1996;98:1381–1388.PubMedCrossRefGoogle Scholar
  37. 37.
    Sikiric P, Separovic J, Anic T, Buljat G, Mikus D, Seiwerth S, et al. The effect of pentadecapeptide BPC 157, H2 blockers and sucralfate on new vessels and new granulation tissue formation. J Physiol (Paris) 1999;93:479–485.CrossRefGoogle Scholar
  38. 38.
    Veljaca M, Lesch CA, Sanchez B, Low J, Guglietta A. Protection of BPC-15 on TNBS-induced colitis in rats: possible mechanisms of action. Gastroenterology 1995;108:936.Google Scholar
  39. 39.
    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
  40. 40.
    Day CS, Buranapanitkit B, Riano FA, Tomaino MM, Somogyi G, Sotereanos DG, et al. Insulin growth factor-1 decreases muscle atrophy following denervation. Microsurgery 2002;22:144–151.PubMedCrossRefGoogle Scholar
  41. 41.
    Mishra S, Fujita T, Lama VN, Nam D, Liao H, Okada M, et al. Carbon monoxide rescues ischemic lungs by interrupting MAPK-driven expression of early growth response 1 gene and its downstream target genes. Proc Natl Acad Sci USA 2006;103:5191–5196.PubMedCrossRefGoogle Scholar
  42. 42.
    Michell CA, McGaechie JK, Grounds MD. The exogenous administration of basic growth factor to mice does not enhance the process of regeneration. Growth Factors 1996;13:37–55.CrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Tomislav Novinscak
    • 1
  • Luka Brcic
    • 2
  • Mario Staresinic
    • 1
  • Ivana Jukic
    • 1
  • Bozo Radic
    • 1
  • Danira Pevec
    • 1
  • Sandro Mise
    • 1
  • Sanja Tomasovic
    • 1
  • Iva Brcic
    • 2
  • Tihomir Banic
    • 1
  • Ana Jakir
    • 1
  • Gojko Buljat
    • 1
  • Tomislav Anic
    • 1
  • Ivan Zoricic
    • 1
  • Zeljko Romic
    • 1
  • Sven Seiwerth
    • 2
  • Predrag Sikiric
    • 1
  1. 1.Department of PharmacologyUniversity of Zagreb Medical SchoolZagrebCroatia
  2. 2.Institute of PathologyUniversity of Zagreb Medical SchoolZagrebCroatia

Personalised recommendations