Journal of Veterinary Clinics (한국임상수의학회지)

The Korean Society of Veterinary Clinics (한국임상수의학회)
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Protective Effect of Platycodin D in the Acute Gastric Ulcer Induced by Ibuprofen in Rats

이부프로펜에 의해 유발된 급성 위궤양에 있어 Platycodin D의 보호효과

  • Yu, Ri (College of Veterinary Medicine, Kyungpook National University) ;
  • Shin, Won-Ho (College of Veterinary Medicine, Kyungpook National University) ;
  • Kim, Sol (College of Veterinary Medicine, Kyungpook National University) ;
  • Son, Kyu-Hee (College of Veterinary Medicine, Kyungpook National University) ;
  • Kwak, Dong-Mi (College of Veterinary Medicine, Kyungpook National University) ;
  • Kim, Sang Ryong (School of Life Sciences & Biotechnology, Institute of Life Science & Biotechnology, Kyungpook National University) ;
  • Ryu, Si-Yun (College of Veterinary Medicine, Chungnam National University) ;
  • Park, Sang-Joon (College of Veterinary Medicine, Kyungpook National University)
  • 유리 (경북대학교 수의과대학) ;
  • 신원호 (경북대학교 수의과대학) ;
  • 김솔 (경북대학교 수의과대학) ;
  • 손규희 (경북대학교 수의과대학) ;
  • 곽동미 (경북대학교 수의과대학) ;
  • 김상룡 (경북대학교 자연과학대학) ;
  • 류시윤 (충남대학교 수의과대학) ;
  • 박상준 (경북대학교 수의과대학)
  • Accepted : 2013.02.14
  • Published : 2013.02.28
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Abstract

Acute gastric ulcer is caused by the unbalance between cell proliferation and apoptosis in gastric mucosa. Platycodin D (PD) has been reported to have a variety of pharmacological properties, including antioxidant and antiin-flammatory effect. In the present study, we investigated the protective effect of PD on the basis of cell proliferation/apoptosis and cyclooxygenase-2 (COX-2) expression in the acute gastric ulcer induced by ibuprofen in Rats. Acute gastric damage was induced by the repeated treatment of ibuprofen (200 mg/kg) with 8 hrs interval in a day. PD was orally administrated at concentrations of 2.5 and 5 mg/kg every day for 5 days before the induction of acute gastric ulcer. Macroscopically, ibuprofen caused a significant increase in the number of lesions in the gastric mucosa. But pretreatment of PD significantly reduced ibuprofen-induced gastric lesion score and prevented excessive mucus depletion in gastric mucosa. Also, pretreatment of PD counteracted significantly Ki-67 decrease in the proliferating zone of gastric glandular portion and highly reduced or delayed apoptotic cells on TUNEL assay. In addition, COX-2 expression was increased in gastric mucosa bearing erosions or ulcers but pretreatment of PD reduced COX-2 expression in gastric lesions. These results show that pretreatment of PD has a protective effect against ibuprofen-induced gastric damage, not only by counteracting a decrease of cell proliferation, but also by inhibiting or delaying apoptosis via regulation of COX-2 within the gastric mucosa.

급성 위궤양은 위점막에서 세포증식과 세포사멸의 불균형으로 발병되어진다. 현재 Platycodin D (PD)는 항산화 및 항염증 등의 다양한 약리효능을 가진다고 보고되고 있다. 본 실험은 ibuprofen에 의해 유발된 급성 위궤양이 전처치한 PD에 의해 위궤양 보호효과를 가지는 가를 알아보기 위해 실시하였다. PD의 효능은 위점막에서의 COX-2의 발현과 더불어 위점막상피세포의 증생과 세포사멸정도에 의해서 평가하였다. 실험군은 정상대조군, ibuprofen 유발 위궤양군, 2.5 mg/kg PD 전처치군, 5 mg/kg PD 전처치군으로 분류하였다. 급성위궤양은 200 mg/kg의 ibuprofen을 하루에 3번 8시간 간격으로 경구 투여하여 유발하였다. PD는 5일간 경구로 하루에 한 번씩 전처치하였다. PD의 전처치가 ibuprofen에 의해 유발된 위궤양 병변을 유의적으로 감소시켰으며 과도한 위점액 분비로 인한 점액질의 소실을 억제하였다. 또한 PD 전처치가 위점막의 상피세포증식층에서 Ki-67 양성세포의 감소 및 세포사멸을 억제하였다. 추가적으로 PD의 전처치가 위궤양에 의해 증가된 COX-2 발현을 감소시켰다. 이상의 연구결과는 PD의 전처치가 ibuprofen에 의해 유발된 위점막손상에 있어 COX-2의 발현조절을 통하여 위점막세포의 증식과 사멸에 관여할 것으로 보여진다.

Keywords

References

  1. Ahn KS, Noh EJ, Zhao HL, Jung SH, Kang SS, Kim YS. Inhibition of inducible nitric oxide synthase and cyclooxygenase II by platycodon grandiflorum saponins via suppression of nuclear-kappaB activation in RAW 264.7 cells. Life Sci 2005; 76: 2315-2328. https://doi.org/10.1016/j.lfs.2004.10.042
  2. Borelli F, Izzo AA. The plant kingdom as a source of antiulcer remedies. Phytother Res 2000; 14: 581-591. https://doi.org/10.1002/1099-1573(200012)14:8<581::AID-PTR776>3.0.CO;2-S
  3. Cao Y, Pearman AT, Zimmerman GA, Mcintyre TM, Prescott SM. Intracellular unesterified arachidonic acid signals apoptosis. Proc Natl Acad Sci 2000; 97: 11280-11285. https://doi.org/10.1073/pnas.200367597
  4. Chan TA, Morin PJ, Vogelstein B, Kinzler KW. Mechanisms underlying nonsteroidal anti-inflammatory drug-mediated apoptosis. Proc Natl Acad Sci 1998; 95: 681-686. https://doi.org/10.1073/pnas.95.2.681
  5. Fries JF. NSAID gastropathy: epidemiology. J Musculoskeletal Med 1991; 8: 21-28.
  6. Hahm KB, Leek J, Kim YS, Kim JH, Cho SW, Yim H, Joo HJ. Quantitative and qualitative usefulness of rebamipide in eradication of Helicobacter pylori. Dig Dis Sci 1998; 43; 192S-197S.
  7. Hall PA, Coates PJ, Ansari B, Hopwood D. Regulation of cell number in the mammalian gastrointestinal tract: the importance of apoptosis. J Cell Sci 1994; 107: 3569-3577.
  8. Hunt R, Bazzoli F. Review article: Should NSAID low-dose aspirin takers be tested routinely for H. pylori infection and treated if positive? Implications for primary risk of ulcer and ulcer relapse after initial healing. Aliment Pharmacol Ther 2004; 19: 9-16. https://doi.org/10.1111/j.0953-0673.2004.01830.x
  9. Jackson LM, Wu KC, Mahida YR, Jenkins D, Hawkey CJ. Cyclooxygenase (COX) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa. Gut 2000; 47: 762-770. https://doi.org/10.1136/gut.47.6.762
  10. Jana NR. NSAIDs and apoptosis. Cell Mol Life Sci 2008; 65: 1295-1301. https://doi.org/10.1007/s00018-008-7511-x
  11. Kim YP, Lee EB, Kim SY, Li D, Ban HS, Lim SS, Shin KH, Ohuchi K. Inhibition of prostaglandin E2 production by platycodin D isolated from the root of platycodon grandiflorum. Planta Med 2001; 67: 362-364. https://doi.org/10.1055/s-2001-14317
  12. Kusuhara H, Matsuyuki H, Matsuura M, Imayoshi T, Okumoto T, Matsui H. Induction of apoptotic DNA fragmentation by nonsteroidal anti-inflammatory drugs in cultured rat gastric mucosal cells. Eur J Pharmacol 1998; 360: 273-280. https://doi.org/10.1016/S0014-2999(98)00679-7
  13. Mizuno H, Sakamoto C, Matsuda K, Wada K, Uchida T, Noguchi H, Akamatsu T, Kasuga M. Induction of cyclooxygenase- 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 1997; 112: 387-397. https://doi.org/10.1053/gast.1997.v112.pm9024292
  14. Moss SF, Calam J, Agarwal B, Wang S, Holt PR. Induction of gastric epithelial apoptosis by Helicobacter pylori. Gut 1996; 38: 498-501. https://doi.org/10.1136/gut.38.4.498
  15. Motilva V, Alarcon de la Lastra C, Bruseghini L, Manuel Herrerias J, Sanchez-Fidalgo S. COX expression and PGE(2) and PGD(2) production in experimental acute and chronic gastric lesions. Int Immunopharmacol 2005; 5: 369-79. https://doi.org/10.1016/j.intimp.2004.10.005
  16. Pandian RS, Anuradha CV, Viswanathan P. Gastroprotective effect of fenugreek seeds on experimental gastric lesions in rats. J Ethnopharmacol 2002; 81: 393-397. https://doi.org/10.1016/S0378-8741(02)00117-4
  17. Piotrowski J, Piotrowski E, Skrodzka D, Slomiany A, Slomiany BL. Gastric mucosal apoptosis induced by ethanol: effect of anti-ulcer agents. Biochem Mol Biol Int 1997; 42: 247-254,
  18. Slomiany BL, Piotrowski J, Slomiany A. Induction of tumor necrosis factor-alpha and apoptosis in gastric mucosal injury by indomethacin: effect of omeprazole and ebrotidine. Scand J Gastroenterol 1997; 32: 638-642. https://doi.org/10.3109/00365529708996511
  19. Wallace JL, Granger DN. The cellular and molecular basis of gastric mucosal defense. FASEB J 1996; 10: 731-740. https://doi.org/10.1096/fasebj.10.7.8635690
  20. Wu CY, Wu MS, Chen YJ, Chen CJ, Lin JT, Chen GH. Influence of COX-2 and local cytokine expression in gastric ulcer mucosa by H. pylori and NSAID. Hepatogastroenterology 2006; 53: 797-803.
  21. Zhu GH, Yang XL, Lai KC, Ching CK, Wong BC, Yuen ST, Ho J, Lam SK. Non-steroidal anti-inflammatory drugs could reverse Helicobacter pylori-induced apoptosis and proliferation in gastric epithelial cells. Dig Dis Sci 1998; 43: 1957-1963. https://doi.org/10.1023/A:1018830408397