Digestive Diseases and Sciences

, Volume 58, Issue 10, pp 2908–2917 | Cite as

Apamin Attenuated Cerulein-Induced Acute Pancreatitis by Inhibition of JNK Pathway in Mice

  • Gi-Sang Bae
  • Kwang-Ho Heo
  • Kyoung-Chel Park
  • Sun Bok Choi
  • Il-Joo Jo
  • Seung-Hee Seo
  • Dong-Goo Kim
  • Joon-Yeon Shin
  • Dae-Gil Kang
  • Ho-Sub Lee
  • Ho-Joon Song
  • Byung-Cheul Shin
  • Sung-Joo Park
Original Article

Abstract

Background/Aim

We have previously reported that bee venom (BV) has a protective role against acute pancreatitis (AP). However, the effects of apamin, the major compound of BV, on AP have not been determined. The aim of this study was to evaluate the effects of apamin on cerulein-induced AP.

Methods

AP was induced via intraperitoneal injection of supramaximal concentrations of the stable cholecystokinin analogue cerulein (50 μg/kg) every hour for 6 times. In the apamin treatment group, apamin was administered subcutaneously (10, 50, or 100 μg/kg) at both 18 and 1 h before the first cerulein injection. The mice were sacrificed at 6 h after the final cerulein injection. Blood samples were obtained to determine serum amylase and lipase levels, as well as cytokine production. The pancreas and lung were rapidly removed for morphologic and histological examination, myeloperoxidase (MPO) assay, and real-time reverse transcription-polymerase chain reaction. Furthermore, we isolated the pancreatic acinar cells to specify the role of apamin in AP.

Results

Pre-treatment with apamin inhibited histological damage, pancreatic weight/body weight ratio, serum level of amylase and lipase, MPO activity, and cytokine production. In addition, apamin treatment significantly inhibited cerulein-induced pancreatic acinar cell death. Furthermore, apamin treatment inhibited the cerulein-induced activation of c-Jun NH2-terminal kinases (JNK).

Conclusions

These results could suggest that apamin could protect against AP by inhibition of JNK activation.

Keywords

Bee venom Apamin Acute pancreatitis Cerulein c-Jun NH2-terminal kinases 

Notes

Acknowledgment

This work was supported by a National Research Foundation of Korea [NRF] grant-funded by the Korean government [MEST]; Contract/Grant Number: 2010-0029498.

Conflict of interest

None.

Supplementary material

10620_2013_2800_MOESM1_ESM.doc (33 kb)
Supplementary material 1 (DOC 33 kb)
10620_2013_2800_MOESM2_ESM.jpg (289 kb)
Supplementary material 2 (JPEG 288 kb)
10620_2013_2800_MOESM3_ESM.jpg (260 kb)
Supplementary material 3 (JPEG 259 kb)
10620_2013_2800_MOESM4_ESM.jpg (157 kb)
Supplementary material 4 (JPEG 157 kb)

References

  1. 1.
    Kusske AM, Rongione AJ, Reber HA. Cytokines and acute pancreatitis. Gastroenterology. 1996;110:639–642.PubMedCrossRefGoogle Scholar
  2. 2.
    Bhatia M, Wong FL, Cao Y, et al. Pathophysiology of acute pancreatitis. Pancreatology. 2005;5:132–144.PubMedCrossRefGoogle Scholar
  3. 3.
    Norman J, Franz M, Messina J, et al. Interleukin-1 receptor antagonist decreases severity of experimental acute pancreatitis. Surgery. 1995;117:648–655.PubMedCrossRefGoogle Scholar
  4. 4.
    Büchler MW, Gloor B, Müller CA, Friess H, Seiler CA, Uhl W. Acute necrotizing pancreatitis: treatment strategy according to the status of infection. Ann Surg. 2000;232:619–626.PubMedCrossRefGoogle Scholar
  5. 5.
    Kwon YB, Lee JD, Lee HJ, et al. Bee venom injection into an acupuncture point reduces arthritis associated edema and nociceptive responses. Pain. 2001;90:271–280.PubMedCrossRefGoogle Scholar
  6. 6.
    Billingham ME, Morley J, Hanson JM, Shipolini RA, Vernin CA. Letter: an anti-inflammatory peptide from bee venom. Nature. 1973;245:163–164.PubMedCrossRefGoogle Scholar
  7. 7.
    Yun SW, Bae GS, Kim MS, et al. Melittin inhibits cerulein-induced acute pancreatitis via inhibition of the JNK pathway. Int Immunopharmacol. 2011;11:2062–2072.PubMedCrossRefGoogle Scholar
  8. 8.
    Kim SJ, Park JH, Kim KH, et al. The protective effect of apamin on LPS/Fat-induced atherosclerotic mice. Evid Based Complement Alternat Med 2012:305454.Google Scholar
  9. 9.
    Yamauchi H, Miura M, Ichinose M, et al. Involvement of apamin-sensitive K+ channels in antigen-induced spasm of guinea-pig isolated trachea. Br J Pharmacol.. 1994;112:958–962.PubMedCrossRefGoogle Scholar
  10. 10.
    Seo SW, Jung WS, Lee SE, et al. Effects of bee venom on cholecystokinin octapeptide-induced acute pancreatitis in rats. Pancreas. 2008;36:22–29.CrossRefGoogle Scholar
  11. 11.
    Kallarackal AJ, Simard JM, Bailey AM. The effect of apamin, a small conductance calcium activated potassium (SK) channel blocker, on a mouse model of neurofibromatosis 1. Behav Brain Res. 2013;237:71–75.PubMedCrossRefGoogle Scholar
  12. 12.
    Castle NA, Haylett DG, Jenkinson DH. Toxins in the characterization of potassium channels. Trends Neurosci. 1989;12:59–65.PubMedCrossRefGoogle Scholar
  13. 13.
    Hsieh YC, Chang PC, Hsueh CH, et al. Apamin-sensitive potassium current modulates action potential duration restitution and arrhythmogenesis of failing rabbit ventricles. Circ Arrhythm Electrophysiol. 2013;6:410–418.PubMedCrossRefGoogle Scholar
  14. 14.
    Dilly S, Philippart F, Lamy C, et al. The interactions of apamin and tetraethylammonium are differentially affected by single mutations in the pore mouth of small conductance calcium-activated potassium (SK) channels. Biochem Pharmacol. 2013;85:560–569.PubMedCrossRefGoogle Scholar
  15. 15.
    Parajuli SP, Hristov KL, Soder RP, Kellett WF, Petkov GV. NS309 decreases rat detrusor smooth muscle membrane potential and phasic contractions by activating SK3 channels. Br J Pharmacol. 2013;168:1611–1625.PubMedCrossRefGoogle Scholar
  16. 16.
    Kallarackal AJ, Simard JM, Bailey AM. The effect of apamin, a small conductance calcium activated potassium (SK) channel blocker, on a mouse model of neurofibromatosis 1. Behav Brain Res. 2013;237:71–75.PubMedCrossRefGoogle Scholar
  17. 17.
    Littleton JT, Ganetzky B. Ion channels and synaptic organization: analysis of the Drosophila genome. Neuron. 2000;26:35–43.PubMedCrossRefGoogle Scholar
  18. 18.
    Patel S, Ramakrishnan L, Rahman T, et al. The endo-lysosomal system as an NAADP-sensitive acidic Ca(2+) store: role for the two-pore channels. Cell Calcium. 2011;50(2):157–167.PubMedCrossRefGoogle Scholar
  19. 19.
    Malinska D, Mirandola SR, Kunz WS. Mitochondrial potassium channels and reactive oxygen species. FEBS Lett. 2010;584:2043–2048.PubMedCrossRefGoogle Scholar
  20. 20.
    Lee WK, Braun M, Langelüddecke C, Thévenod F. Cyclosporin a, but not FK506, induces osmotic lysis of pancreas zymogen granules, intra-acinar enzyme release, and lysosome instability by activating K+ channel. Pancreas. 2012;41:596–604.PubMedCrossRefGoogle Scholar
  21. 21.
    Venglovecz V, Hegyi P, Rakonczay Z Jr, et al. Pathophysiological relevance of apical large-conductance Ca2+-activated potassium channels in pancreatic duct epithelial cells. Gut. 2011;60:361–369.PubMedCrossRefGoogle Scholar
  22. 22.
    Yang K, Ding YX, Chin WC. K+-induced ion-exchanges trigger trypsin activation in pancreas acinar zymogen granules. Arch Biochem Biophys. 2007;459:256–263.PubMedCrossRefGoogle Scholar
  23. 23.
    Fan M, Chambers TC. Role of MAPKs in the response of tumor cells to chemotherapy. Drug Resist Updat. 2001;4:253–267.PubMedCrossRefGoogle Scholar
  24. 24.
    Gukovsky I, Gukovskaya AS, Blinman TA, Zaninovic V, Pandol SJ. Early NF-kappaB activation is associated with hormone-induced pancreatitis. Am J Physiol. 1998;275:1402–1414.Google Scholar
  25. 25.
    Lee J, Seo J, Kim H, Chung JB, Kim KH. Signal transduction of cerulein induced cytokine expression and apoptosis pancreatic acinar cells. Ann NY Acad Sci. 2003;1010:104–108.PubMedCrossRefGoogle Scholar
  26. 26.
    Bae GS, Park HJ, Kim DY, et al. Nardostachys jatamansi protects against cerulein-induced acute pancreatitis. Pancreas. 2010;39:520–529.PubMedCrossRefGoogle Scholar
  27. 27.
    Kim TH, Bae GS, Oh HJ, et al. 2′,4′,6′-Tris(methoxymethoxy) chalcone (TMMC) attenuates the severity of cerulein-induced acute pancreatitis and associated lung injury. Am J Physiol Gastrointest Liver Physiol. 2011;301:G694–G706.PubMedCrossRefGoogle Scholar
  28. 28.
    Bae GS, Kim MS, Jeong J, et al. Piperine ameliorates the severity of cerulein-induced acute pancreatitis by inhibiting the activation of mitogen activated protein kinases. Biochem Biophys Res Commun. 2011;410:382–388.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Gi-Sang Bae
    • 1
  • Kwang-Ho Heo
    • 2
  • Kyoung-Chel Park
    • 4
  • Sun Bok Choi
    • 4
  • Il-Joo Jo
    • 4
  • Seung-Hee Seo
    • 4
  • Dong-Goo Kim
    • 4
  • Joon-Yeon Shin
    • 4
  • Dae-Gil Kang
    • 1
    • 5
  • Ho-Sub Lee
    • 1
    • 5
  • Ho-Joon Song
    • 4
  • Byung-Cheul Shin
    • 2
    • 3
  • Sung-Joo Park
    • 1
    • 4
  1. 1.Hanbang Body-fluid Research CenterWonkwang UniversityIksanSouth Korea
  2. 2.Department of Rehabilitation Medicine of Korean Medicine, Spine & Joint CenterPusan National University Korean Medicine HospitalYangsanSouth Korea
  3. 3.Division of Clinical Medicine, School of Korean MedicinePusan National UniversityYangsanSouth Korea
  4. 4.Department of Herbology, College of Oriental MedicineWonkwang UniversityIksanSouth Korea
  5. 5.Professional Graduate School of Oriental MedicineWonkwang UniversityIksanSouth Korea

Personalised recommendations