Skip to main content

Protective Effects of Garlic Extract, PMK-S005, Against Nonsteroidal Anti-inflammatory Drugs–Induced Acute Gastric Damage in Rats

Abstract

Background

PMK-S005 is synthetic s-allyl-l-cysteine (SAC), a sulfur-containing amino acid, which was initially isolated from garlic. The antioxidant and anti-inflammation activities of SAC have been demonstrated in diverse experimental animal models.

Aims

The purpose of this study was to investigate the gastroprotective effects of PMK-S005 against NSAIDs-induced acute gastric damage in rats.

Methods

Eight-week SD rats were pretreated with PMK-S005 (1, 5, or 10 mg/kg) or rebamipide (50 mg/kg) 1 h before administration of NSAIDs including aspirin (200 mg/kg), diclofenac (80 mg/kg), and indomethacin (40 mg/kg). After 4 h, the gross ulcer index, histological index, and gastric mucus level were determined. Myeloperoxidase (MPO), TNF-α, IL-1β, PGE2, and LTB4 levels were estimated in the gastric mucosal tissue by ELISA. Protein expressions of cPLA2, COX-1, and COX-2 were assessed by Western blot analysis.

Results

Pretreatment with PMK-S005 significantly attenuated the NSAIDs-induced gastric damage and increased the gastric mucus level. In addition, PMK-S005 attenuated increases in MPO, TNF-α, and IL-1β production. The expressions of cPLA2 and COX-2 induced by NSAIDs were decreased by PMK-S005 pretreatment. PMK-S005 did not cause suppression of PGE2 synthesis induced by NSAIDs, but LTB4 production was significantly suppressed by PMK-S005. The effects of PMK-S005 were consistently maximized at a concentration of 5 mg/kg, which were frequently superior to those of rebamipide.

Conclusions

These results strongly suggest that PMK-S005 can be a useful gastroprotective agent against acute gastric mucosal damage by suppressing proinflammatory cytokines, down-regulating cPLA2, COX-2 and LTB4 expression, and increasing the synthesis of mucus.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  1. 1.

    Laine L, Takeuchi K, Tarnawski A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology. 2008;135:41–60.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Konturek SJ, Konturek PC, Brzozowski T, Konturek JW, Pawlik WW. From nerves and hormones to bacteria in the stomach; Nobel prize for achievements in gastrology during last century. J Physiol Pharmacol. 2005;56:507–530.

    CAS  PubMed  Google Scholar 

  3. 3.

    Sostres C, Gargallo CJ, Arroyo MT, Lanas A. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Pract Res Clin Gastroenterol. 2010;24:121–132.

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Pilotto A. Aging and upper gastrointestinal disorders. Best Pract Res Clin Gastroenterol. 2004;18:73–81.

    PubMed  Article  Google Scholar 

  5. 5.

    Zullo A, Hassan C, Campo SM, Morini S. Bleeding peptic ulcer in the elderly: risk factors and prevention strategies. Drugs Aging. 2007;24:815–828.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Higham J, Kang JY, Majeed A. Recent trends in admissions and mortality due to peptic ulcer in England: increasing frequency of haemorrhage among older subjects. Gut. 2002;50:460–464.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  7. 7.

    Ishihara M, Ito M. Influence of aging on gastric ulcer healing activities of cimetidine and omeprazole. Eur J Pharmacol. 2002;444:209–215.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Bae S, Kim N, Kang JM, et al. Incidence and 30-day mortality of peptic ulcer bleeding in Korea. Eur J Gastroenterol Hepatol. 2012;24:675–682.

    PubMed  Article  Google Scholar 

  9. 9.

    Bae S, Shim KN, Kim N, et al. The incidence and short-term mortality of perforated peptic ulcer in Korea: a population-based study. J Epidemiol. 2012;22:508–516.

    PubMed Central  PubMed  Article  Google Scholar 

  10. 10.

    Poynter D, Pick CR, Harcourt RA, et al. Association of long lasting unsurmountable histamine H2 blockade and gastric carcinoid tumours in the rat. Gut. 1985;26:1284–1295.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  11. 11.

    Penston J, Wormsley KG. Adverse reactions and interactions with H2-receptor antagonists. Med Toxicol. 1986;1:192–216.

    CAS  PubMed  Google Scholar 

  12. 12.

    Eom CS, Park SM, Myung SK, Yun JM, Ahn JS. Use of acid-suppressive drugs and risk of fracture: a meta-analysis of observational studies. Ann Fam Med. 2011;9:257–267.

    PubMed Central  PubMed  Article  Google Scholar 

  13. 13.

    Sheen E, Triadafilopoulos G. Adverse effects of long-term proton pump inhibitor therapy. Dig Dis Sci. 2011;56:931–950.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Kang JM, Kim N, Kim JH, et al. Effect of aging on gastric mucosal defense mechanism: ROS, apoptosis, angiogenesis and sensory neuron. Am J Physiol Gastrointest Liver Physiol. 2010;299:G1147–G1153.

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Kim JI, Kim SG, Kim N, et al. Korean College of Helicobacter and Upper Gastrointestinal Research Study Group. Changing prevalence of upper gastrointestinal disease in 28,893 Koreans from 1995 to 2005. Euro J Gastroenterol Hepatol. 2009;21:787–793.

    Article  Google Scholar 

  16. 16.

    Laloo D, Prasad SK, Krishnamurthy S, Hemalatha S. Gastroprotective activity of ethanolic root extract of Potentilla fulgens Wall. ex Hook. J Ethnopharmacol. 2013;146:505–514.

    PubMed  Article  Google Scholar 

  17. 17.

    Kang JM, Kim N, Kim B, et al. Gastroprotective action of Cochinchina momordica seed extract is mediated by activation of CGRP and inhibition of cPLA(2)/5-LOX pathway. Dig Dis Sci. 2009;54:2549–2560.

    PubMed  Article  Google Scholar 

  18. 18.

    Ray B, Chauhan NB, Lahiri DK. Oxidative insults to neurons and synapse are prevented by aged garlic extract and S-allyl-l-cysteine treatment in the neuronal culture and APP-Tg mouse model. J Neurochem. 2011;117:388–402.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  19. 19.

    Mong MC, Yin MC. Nuclear factor κB-dependent anti-inflammatory effects of s-allyl cysteine and s-propyl cysteine in kidney of diabetic mice. J Agric Food Chem. 2012;60:3158–3165.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Nam SY, Kim N, Lee CS, et al. Gastric mucosal protection via enhancement of MUC5AC and MUC6 by geranylgeranylacetone. Dig Dis Sci. 2005;50:2110–2120.

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Lacy ER, Ito S. Microscopic analysis of ethanol damage to rat gastric mucosa after treatment with a prostaglandin. Gastroenterology. 1982;83:619–625.

    CAS  PubMed  Google Scholar 

  22. 22.

    Kitagawa H, Takeda F, Kohei H. A simple method for estimation of gastric mucus and effects of antiulcerogenic agents on the decrease in mucus during water-immersion stress in rats. Arzneimittelforschung. 1986;36:1240–1244.

    CAS  PubMed  Google Scholar 

  23. 23.

    Nishida K, Ohta Y, Ishiguro I. Teprenone, an anti-ulcer agent, increases gastric mucosal mucus level via nitric oxide in rats. Jpn J Pharmacol. 1998;78:519–522.

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Musumba C, Pritchard DM, Pirmohamed M. Review article: cellular and molecular mechanisms of NSAID-induced peptic ulcers. Aliment Pharmacol Ther. 2009;30:517–531.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Thomson M, Ali M. Garlic [Allium sativum]: a review of its potential use as an anti-cancer agent. Curr Cancer Drug Targets. 2003;3:67–81.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Khatua TN, Adela R, Banerjee SK. Garlic and cardioprotection: insights into the molecular mechanisms. Can J Physiol Pharmacol. 2013;91:448–458.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Li L, Sun T, Tian J, Yang K, Yi K, Zhang P. Garlic in clinical practice: an evidence-based overview. Crit Rev Food Sci Nutr. 2013;53:670–681.

    PubMed  Article  Google Scholar 

  28. 28.

    Butt MS, Sultan MT, Butt MS, Iqbal J. Garlic: nature’s protection against physiological threats. Crit Rev Food Sci Nutr. 2009;49:538–551.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Kodai S, Takemura S, Minamiyama Y, et al. S-allyl cysteine prevents CCl(4)-induced acute liver injury in rats. Free Radic Res. 2007;41:489–497.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Ried K, Frank OR, Stocks NP. Aged garlic extract lowers blood pressure in patients with treated but uncontrolled hypertension: a randomised controlled trial. Maturitas. 2010;67:144–150.

    PubMed  Article  Google Scholar 

  31. 31.

    Choi SM, Shin JH, Kang KK, Ahn BO, Yoo M. Gastroprotective effects of DA-6034, a new flavonoid derivative, in various gastric mucosal damage models. Dig Dis Sci. 2007;52:3075–3080.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Choi HS, Lim JY, Chun HJ, Lee M, et al. The effect of polaprezinc on gastric mucosal protection in rats with ethanol-induced gastric mucosal damage: comparison study with rebamipide. Life Sci. 2013;93:69–77.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Arakawa T, Higuchi K, Fujiwara Y, et al. 15th anniversary of rebamipide: looking ahead to the new mechanisms and new applications. Dig Dis Sci. 2005;50:S3–S11.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Kleine A, Kluge S, Peskar BM. Stimulation of prostaglandin biosynthesis mediates gastroprotective effect of rebamipide in rats. Dig Dis Sci. 1993;38:1441–1449.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Yoshikawa T, Naito Y, Tanigawa T, Kondo M. Free radical scavenging activity of the novel anti-ulcer agent rebamipide studied by electron spin resonance. Arzneimittelforschung. 1993;43:363–366.

    CAS  PubMed  Google Scholar 

  36. 36.

    Suzuki M, Miura S, Mori M, et al. Rebamipide, a novel antiulcer agent, attenuates Helicobacter pylori induced gastric mucosal cell injury associated with neutrophil derived oxidants. Gut. 1994;35:1375–1378.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  37. 37.

    Suzuki H, Mori M, Kai A, et al. Effect of rebamipide on H. pylori-associated gastric mucosal injury in Mongolian gerbils. Dig Dis Sci. 1998;43:181S–187S.

    CAS  PubMed  Google Scholar 

  38. 38.

    Nishizawa T, Suzuki H, Nakagawa I, Minegishi Y, et al. Rebamipide-promoted restoration of gastric mucosal sonic hedgehog expression after early Helicobacter pylori eradication. Digestion. 2009;79:259–262.

    PubMed  Article  Google Scholar 

  39. 39.

    Terano A, Arakawa T, Sugiyama T, Suzuki H, Rebamipide Clinical Study Group, et al. Rebamipide, a gastro-protective and anti-inflammatory drug, promotes gastric ulcer healing following eradication therapy for Helicobacter pylori in a Japanese population: a randomized, double-blind, placebo-controlled trial. J Gastroenterol. 2007;42:690–693.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Tanigawa T, Pai R, Arakawa T, Tarnawski AS. Rebamipide inhibits gastric cancer cell growth. Dig Dis Sci. 2007;52:240–247.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Seo PJ, Kim N, Kim JH, et al. Comparison of indomethacin, diclofenac and aspirin-induced gastric damage according to age in rats. Gut Liver. 2012;6:210–217.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  42. 42.

    Beck PL, Xavier R, Lu N, et al. Mechanisms of NSAID-induced gastrointestinal injury defined using mutant mice. Gastroenterology. 2000;119:699–705.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Asako H, Kubes P, Wallace J, Gaginella T, Wolf RE, Granger DN. Indomethacin-induced leukocyte adhesion in mesenteric venules: role of lipoxygenase products. Am J Physiol. 1992;262:G903–G908.

    CAS  PubMed  Google Scholar 

  44. 44.

    Suzuki H, Nishizawa T, Tsugawa H, Mogami S, Hibi T. Roles of oxidative stress in stomach disorders. J Clin Biochem Nutr. 2012;50:35–39.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  45. 45.

    Lee BH, Kim N, Nam RH, et al. Difficult establishment of chronic NSAID-induced gastric inflammation rat model due to gastric adaptation and small bowel damage. Korean J Gastroenterol. 2014;63:341–347.

    PubMed  Article  Google Scholar 

  46. 46.

    Sinha M, Gautam L, Shukla PK, Kaur P, Sharma S, Singh TP. Current perspectives in NSAID-induced gastropathy. Mediat Inflamm. 2013;2013:258209.

  47. 47.

    Colín-González AL, Santana RA, Silva-Islas CA, Chánez-Cárdenas ME, Santamaría A, Maldonado PD. The antioxidant mechanisms underlying the aged garlic extract- and S-allylcysteine-induced protection. Oxid Med Cell Longev. 2012;2012:907162.

Download references

Acknowledgments

This work was supported by Chungcheong leading industry promotion project of the Korean Ministry of Knowledge Economy.

Conflict of interest

None of the authors have any conflict of interest or financial arrangements that could potentially influence the described research.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Nayoung Kim.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Choi, Y.J., Kim, N., Lee, J.Y. et al. Protective Effects of Garlic Extract, PMK-S005, Against Nonsteroidal Anti-inflammatory Drugs–Induced Acute Gastric Damage in Rats. Dig Dis Sci 59, 2927–2934 (2014). https://doi.org/10.1007/s10620-014-3370-5

Download citation

Keywords

  • s-allyl-l-cysteine (SAC)
  • Gastroprotection
  • Anti-inflammatory agent
  • Rat
  • NSAID