Skip to main content
SpringerLink
Log in

The effect of synthetic ceramide analogues on gastritis and esophagitis in rats

  • Research Article
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

The effects of ceremide analogues on esophagitis and gastritis in rats were examined. Gastritis induced by indomethacin was significantly reduced after CY3325 and CY3723 treatment, whereas other analogues had no effect. The amount of malondialdehyde in gastritis was significantly reduced by CY3325 or CY 3723. CY3325 or CY 3723 decreased the glutathione levels in gastritis. The myeloperoxidase level in gastritis is increased, and its increment was decreased by CY3325 and CY3723. In reflux esophagitis, the ulceration was decreased by CY3325, CY3723. The gastric volume and acid output are reduced, whereas the pH value is increased by CY3325 or CY3723 after esophagitis. These results suggest that ceramide analogues, CY3325 and CY3723, can prevent the development of gastritis and reflux esophagitis in rats.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

AA:

Arachidonic acid

Ach:

Acethylcholine

CAT:

Catalases

DAG:

Diacylglycerol

LES:

Lower esophageal sphincter

MAPK:

Mitogen-activated protein kinase

MDA:

Malondialdehyde

MPO:

Myeloperoxidase

NSAIDs:

Non-steroidal anti-inflammatory drugs

NOS:

Nitric oxide synthase

PC:

Phosphatidylcholine

PKC:

Protein kinase C

ROS:

Reactive oxygen

SOD:

Superoxide dismutases

SMase:

Sphingomyelinase

TBARS:

Thiobarbituric acid-reactive substances

TCA:

Trichloroacetic acid

References

  • Andersson D, Kotarsky K, Wu J, Agace W, Duan RD (2009) Expression of alkaline sphingomyelinase in yeast cells and anti-inflammatory effects of the expressed enzyme in a rat colitis model. Dig Dis Sci 54:1440–1448

    Article  CAS  PubMed  Google Scholar 

  • Becker KA, Riethmuller J, Luth A, Doring G, Kleuser B and Gulbins E (2009) Acid Sphingomyelinase Inhibitors Normalize Pulmonary Ceramide and Inflammation in Cystic Fibrosis. Am J Respir Cell Mol Biol

  • Bell NJ, Hunt RH (1992) Role of gastric acid suppression in the treatment of gastro-oesophageal reflux disease. Gut 33:118–124

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bell NJ, Burget D, Howden CW, Wilkinson J, Hunt RH (1992) Appropriate acid suppression for the management of gastro-oesophageal reflux disease. Digestion 51(Suppl 1):59–67

    PubMed  Google Scholar 

  • Beutler E, Duron O, Kelly BM (1963) Improved method for the determination of blood glutathione. J Lab Clin Med 61:882–888

    CAS  PubMed  Google Scholar 

  • Biancani P, Sohn UD, Rich HG, Harnett KM, Behar J (1997) Signal transduction pathways in esophageal and lower esophageal sphincter circular muscle. Am J Med 103:23S–28S

    Article  CAS  PubMed  Google Scholar 

  • Bose R, Verheij M, Haimovitz-Friedman A, Scotto K, Fuks Z, Kolesnick R (1995) Ceramide synthase mediates daunorubicin-induced apoptosis: an alternative mechanism for generating death signals. Cell 82:405–414

    Article  CAS  PubMed  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • Buege JA, Aust SD (1978) Microsomal lipid peroxidation. Methods Enzymol 52:302–310

    Article  CAS  PubMed  Google Scholar 

  • Cao W, Sohn UD, Bitar KN, Behar J, Biancani P, Harnett KM (2003) MAPK mediates PKC-dependent contraction of cat esophageal and lower esophageal sphincter circular smooth muscle. Am J Physiol Gastrointest Liver Physiol 285:G86–G95

    Article  CAS  PubMed  Google Scholar 

  • Duan RD (2006) Alkaline sphingomyelinase: an old enzyme with novel implications. Biochim Biophys Acta 1761:281–291

    Article  CAS  PubMed  Google Scholar 

  • Fensome AC, Rodrigues-Lima F, Josephs M, Paterson HF, Katan M (2000) A neutral magnesium-dependent sphingomyelinase isoform associated with intracellular membranes and reversibly inhibited by reactive oxygen species. J Biol Chem 275:1128–1136

    Article  CAS  PubMed  Google Scholar 

  • Geeraert L, Mannaerts GP, van Veldhoven PP (1997) Conversion of dihydroceramide into ceramide: involvement of a desaturase. Biochem J 327(Pt 1):125–132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Granger DN, Korthuis RJ (1995) Physiologic mechanisms of postischemic tissue injury. Annu Rev Physiol 57:311–332

    Article  CAS  PubMed  Google Scholar 

  • Grisham MB, Benoit JN, Granger DN (1990) Assessment of leukocyte involvement during ischemia and reperfusion of intestine. Methods Enzymol 186:729–742

    Article  CAS  PubMed  Google Scholar 

  • Hannun YA (1996) Functions of ceramide in coordinating cellular responses to stress. Science 274:1855–1859

    Article  CAS  PubMed  Google Scholar 

  • Hirschberg K, Rodger J, Futerman AH (1993) The long-chain sphingoid base of sphingolipids is acylated at the cytosolic surface of the endoplasmic reticulum in rat liver. Biochem J 290(Pt 3):751–757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hosey MM, DebBurman SK, Pals-Rylaarsdam R, Richardson RM, Benovic JL (1996) The role of G-protein coupled receptor kinases in the regulation of muscarinic cholinergic receptors. Prog Brain Res 109:169–179

    Article  CAS  PubMed  Google Scholar 

  • Jung J, Nam Y, Sohn UD (2012) Inhibitory effects of ECQ on indomethacin-induced gastric damage in rats. Korean J Physiol Pharmacol 16:399–404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang HY, Lee TS, Lee YP, Lee DW, La HO, Song HJ, Sohn UD (2001) Interaction of calmodulin- and PKC-dependent contractile pathways in cat lower esophageal sphincter (LES). Arch Pharmacal Res 24:546–551

    Article  CAS  Google Scholar 

  • Kim SG, Kim SO (2004) PKC downstream of Pl3-kinase regulates peroxynitrite formation for Nrf2-mediated GSTA2 induction. Arch Pharmacal Res 27:757–762

    Article  CAS  Google Scholar 

  • Kolesnick R (1992) Ceramide: a novel second messenger. Trends Cell Biol 2:232–236

    Article  CAS  PubMed  Google Scholar 

  • Lee DW, Park SY, Ryu JS, Kim SH, Im CU, Choi SH, Lee SE, Ko SK, Sohn UD (2008) Relaxation effect of synthetic ceramide analogues in cat esophageal smooth muscle cells. Korean J Physiol Pharmacol 12:137–142

    Article  PubMed  PubMed Central  Google Scholar 

  • Lee DH, Kim SH, Ahn KH, Kim SK, Choi JM, Ji JE, Won JH, Park YH, Lim C, Kim S, Kim DK (2011) Identification and evaluation of neutral sphingomyelinase 2 inhibitors. Arch Pharmacal Res 34:229–236

    Article  CAS  Google Scholar 

  • Liscovitch M, Cantley LC (1994) Lipid second messengers. Cell 77:329–334

    Article  CAS  PubMed  Google Scholar 

  • Macchia M, Barontini S, Bertini S, Di Bussolo V, Fogli S, Giovannetti E, Grossi E, Minutolo F, Danesi R (2001) Design, synthesis, and characterization of the antitumor activity of novel ceramide analogues. J Med Chem 44:3994–4000

    Article  CAS  PubMed  Google Scholar 

  • Martin SF, Sawai H, Villalba JM, Hannun YA (2007) Redox regulation of neutral sphingomyelinase-1 activity in HEK293 cells through a GSH-dependent mechanism. Arch Biochem Biophys 459:295–300

    Article  CAS  PubMed  Google Scholar 

  • Merrill AH Jr, Schmelz EM, Dillehay DL, Spiegel S, Shayman JA, Schroeder JJ, Riley RT, Voss KA, Wang E (1997) Sphingolipids–the enigmatic lipid class: biochemistry, physiology, and pathophysiology. Toxicol Appl Pharmacol 142:208–225

    Article  CAS  PubMed  Google Scholar 

  • Michel C, van Echten-Deckert G, Rother J, Sandhoff K, Wang E, Merrill AH Jr (1997) Characterization of ceramide synthesis. A dihydroceramide desaturase introduces the 4,5-trans-double bond of sphingosine at the level of dihydroceramide. J Biol Chem 272:22432–22437

    Article  CAS  PubMed  Google Scholar 

  • Min YS, Yim SH, Bai KL, Choi HJ, Jeong JH, Song HJ, Park SY, Ham I, Whang WK, Sohn UD (2005) The effects of apigenin-7-O-beta-d-glucuronopyranoside on reflux oesophagitis and gastritis in rats. Auton Autacoid Pharmacol 25:85–91

    Article  CAS  PubMed  Google Scholar 

  • Min YS, Lee SE, Hong ST, Kim HS, Choi BC, Sim SS, Whang WK, Sohn UD (2009) The inhibitory effect of quercetin-3-o-beta-d-glucuronopyranoside on gastritis and reflux esophagitis in rats. Korean J Physiol Pharmacol 13:295–300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nahrlich L, Mainz JG, Adams C, Engel C, Herrmann G, Icheva V, Lauer J, Deppisch C, Wirth A, Unger K, Graepler-Mainka U, Hector A, Heyder S, Stern M, Doring G, Gulbins E, Riethmuller J (2013) Therapy of CF-patients with amitriptyline and placebo–a randomised, double-blind, placebo-controlled phase IIb multicenter, cohort-study. Cell Physiol Biochem 31:505–512

    Article  PubMed  Google Scholar 

  • Naito Y, Yoshikawa T, Yoshida N, Kondo M (1998) Role of oxygen radical and lipid peroxidation in indomethacin-induced gastric mucosal injury. Dig Dis Sci 43:30S–34S

    CAS  PubMed  Google Scholar 

  • Nakamura K, Ozawa Y, Furuta Y, Miyazaki H (1982) Effects of sodium polyacrylate (PANa) on acute esophagitis by gastric juice in rats. Jpn J Pharmacol 32:445–456

    Article  CAS  PubMed  Google Scholar 

  • Naya MJ, Pereboom D, Ortego J, Alda JO, Lanas A (1997) Superoxide anions produced by inflammatory cells play an important part in the pathogenesis of acid and pepsin induced oesophagitis in rabbits. Gut 40:175–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Okabe S, Takinami Y, Iwata K, Yanagawa T (1995) Mucosal protective effect of leminoprazole on reflux esophagitis induced in rats. Jpn J Pharmacol 69:317–323

    Article  CAS  PubMed  Google Scholar 

  • Okazaki M (1989) An acoustical analysis of TMJ sounds and its clinical importance. Shoni Shikagaku Zasshi 27:101–119

    CAS  PubMed  Google Scholar 

  • Park IN, Cho IJ, Kim SG (2004) Ceramide, an apoptotic rheostat, inhibits CCAAT/enhancer binding protein-beta and NF-E2-related factor-2 activation: the role in glutathione S-transferase A2 gene repression. Drug Metab Dispos 32:893–897

    CAS  PubMed  Google Scholar 

  • Pihan G, Regillo C, Szabo S (1987) Free radicals and lipid peroxidation in ethanol- or aspirin-induced gastric mucosal injury. Dig Dis Sci 32:1395–1401

    Article  CAS  PubMed  Google Scholar 

  • Rodrigues-Lima F, Fensome AC, Josephs M, Evans J, Veldman RJ, Katan M (2000) Structural requirements for catalysis and membrane targeting of mammalian enzymes with neutral sphingomyelinase and lysophospholipid phospholipase C activities. analysis by chemical modification and site-directed mutagenesis. J Biol Chem 275:28316–28325

    CAS  PubMed  Google Scholar 

  • Rutkute K, Asmis RH, Nikolova-Karakashian MN (2007) Regulation of neutral sphingomyelinase-2 by GSH: a new insight to the role of oxidative stress in aging-associated inflammation. J Lipid Res 48:2443–2452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakata A, Ochiai T, Shimeno H, Hikishima S, Yokomatsu T, Shibuya S, Toda A, Eyanagi R, Soeda S (2007a) Acid sphingomyelinase inhibition suppresses lipopolysaccharide-mediated release of inflammatory cytokines from macrophages and protects against disease pathology in dextran sulphate sodium-induced colitis in mice. Immunology 122:54–64

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sakata A, Yasuda K, Ochiai T, Shimeno H, Hikishima S, Yokomatsu T, Shibuya S, Soeda S (2007b) Inhibition of lipopolysaccharide-induced release of interleukin-8 from intestinal epithelial cells by SMA, a novel inhibitor of sphingomyelinase and its therapeutic effect on dextran sulphate sodium-induced colitis in mice. Cell Immunol 245:24–31

    Article  CAS  PubMed  Google Scholar 

  • Sbrissa D, Yamada H, Hajra A, Bitar KN (1997) Bombesin-stimulated ceramide production and MAP kinase activation in rabbit rectosigmoid smooth muscle cells. Am J Physiol 272:G1615–G1625

    CAS  PubMed  Google Scholar 

  • Schwandner R, Wiegmann K, Bernardo K, Kreder D, Kronke M (1998) TNF receptor death domain-associated proteins TRADD and FADD signal activation of acid sphingomyelinase. J Biol Chem 273:5916–5922

    Article  CAS  PubMed  Google Scholar 

  • Shin CY, Lee YP, Lee TS, Song HJ, Sohn UD (2002) C(2)-ceramide-induced circular smooth muscle cell contraction involves PKC-epsilon and p44/p42 MAPK activation in cat oesophagus mitogen-activated protein kinase. Cell Signal 14:925–932

    Article  CAS  PubMed  Google Scholar 

  • Shin CY, Lee WJ, Choi JW, Choi MS, Park GH, Yoo BK, Han SY, Ryu JR, Choi EY, Ko KH (2007) Role of p38 MAPK on the down-regulation of matrix metalloproteinase-9 expression in rat astrocytes. Arch Pharm Res 30:624–633

    Article  CAS  PubMed  Google Scholar 

  • Sohn UD, Chiu TT, Bitar KN, Hillemeier C, Behar J, Biancani P (1994) Calcium requirements for acetylcholine-induced contraction of cat esophageal circular muscle cells. Am J Physiol 266:G330–G338

    CAS  PubMed  Google Scholar 

  • Sohn UD, Han B, Tashjian AH Jr, Behar J, Biancani P (1995) Agonist-independent, muscle-type-specific signal transduction pathways in cat esophageal and lower esophageal sphincter circular smooth muscle. J Pharmacol Exp Ther 273:482–491

    CAS  PubMed  Google Scholar 

  • Sohn UD, Zoukhri D, Dartt D, Sergheraert C, Harnett KM, Behar J, Biancani P (1997) Different protein kinase C isozymes mediate lower esophageal sphincter tone and phasic contraction of esophageal circular smooth muscle. Mol Pharmacol 51:462–470

    CAS  PubMed  Google Scholar 

  • Sohn UD, Park JH, Lee TS, Shin CY, Jeong JH, Kim JH, Je HD, Dartt DA, Zoukhri D, Choi HC, Lee KY (2003) Differential regulation by Ca(2+) of calmodulin- and PKC-dependent contractile pathways in cat lower oesophageal sphincter. Auton Autacoid Pharmacol 23:307–317

    Article  CAS  PubMed  Google Scholar 

  • Stein HJ, Hinder RA, Oosthuizen MM (1990) Gastric mucosal injury caused by hemorrhagic shock and reperfusion: protective role of the antioxidant glutathione. Surgery 108:467–473 (discussion 473-464)

    CAS  PubMed  Google Scholar 

  • Takahashi T, Morita K, Akagi R, Sassa S (2004) Heme oxygenase-1: a novel therapeutic target in oxidative tissue injuries. Curr Med Chem 11:1545–1561

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi K, Ueshima K, Hironaka Y, Fujioka Y, Matsumoto J, Okabe S (1991) Oxygen free radicals and lipid peroxidation in the pathogenesis of gastric mucosal lesions induced by indomethacin in rats relation to gastric hypermotility. Digestion 49:175–184

    Article  CAS  PubMed  Google Scholar 

  • Tanaka J, Yuda Y (1996) Lipid peroxidation in gastric mucosal lesions induced by indomethacin in rat. Biol Pharm Bull 19:716–720

    Article  CAS  PubMed  Google Scholar 

  • Witty JP, Bridgham JT, Johnson AL (1996) Induction of apoptotic cell death in hen granulosa cells by ceramide. Endocrinology 137:5269–5277

    CAS  PubMed  Google Scholar 

  • Yan XM, Joo MJ, Lim JC, Whang WK, Sim SS, Im C, Kim HR, Lee SY, Kim IK, Sohn UD (2011) The effect of quercetin-3-O-beta-D-glucuronopyranoside on indomethacin-induced gastric damage in rats via induction of mucus secretion and down-regulation of ICAM-1 expression. Arch Pharmacal Res 34:1527–1534

    Article  CAS  Google Scholar 

  • Zimmerman BJ, Granger DN (1994) Oxygen free radicals and the gastrointestinal tract: role in ischemia-reperfusion injury. Hepatogastroenterology 41:337–342

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The design of ceramide analogues was supported from professor, CB Yim, Department of Medicinal Chemistry, College of Pharmacy, Chung-Ang University, Seoul 156-756, Republic of Korea. This research was partially supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (no. 2011-0012139).

Author information

Author notes

    Authors and Affiliations

    1. Department of Pharmacology, College of Pharmacy, Chung-Ang University, Seoul, 156-756, Republic of Korea

      Sung Hyo Kim, Seung In Um, Yoonjin Nam, Sun Young Park, Uy Dong Sohn & Sang Joon Lee

    2. Department of Pharmacology, College of Pharmacy, Catholic University of Daegu, Gyeongsan, 38430, Republic of Korea

      Je Hyun Dong

    3. Department of Oriental Medical Food & Nutrition, Semyung University, Jecheon, Choongbuk, 27136, Republic of Korea

      Sung Kwon Ko

    Authors
    1. Sung Hyo Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Seung In Um
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Yoonjin Nam
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Sun Young Park
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Je Hyun Dong
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Sung Kwon Ko
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Uy Dong Sohn
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Sang Joon Lee
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding authors

    Correspondence to Uy Dong Sohn or Sang Joon Lee.

    Additional information

    Sung Hyo Kim and Seung In Um have been contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Kim, S.H., Um, S.I., Nam, Y. et al. The effect of synthetic ceramide analogues on gastritis and esophagitis in rats. Arch. Pharm. Res. 39, 1313–1323 (2016). https://doi.org/10.1007/s12272-016-0792-y

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s12272-016-0792-y

    Keywords

    Search

    Navigation