Abstract
Aim
This study aimed to demonstrate the role of serotonin 7 receptor (5-HT7) and the effects of 5-HT7 agonists and antagonists in an indomethacin-induced gastric ulcer.
Material and method
Male albino Wistar rats (n = 60) were used in the experiments. LP44 (5-HT7 agonist) and SB269970 (5-HT7 antagonist) were administered at 10 mg/kg as a pre-treatment. One hour after the drug treatments, 25 mg/kg of indomethacin (INDO) was administered to all groups except the healthy control group. Six hours after indomethacin administration, all the rats were euthanized.
Results
We analyzed the iNOS, eNOS, and 5-HT7 receptor mRNA levels in the stomach tissue of rats by real-time PCR. 5-HT7 mRNA expression was increased in the INDO group compared to the healthy group. LP44 administration exerted a significant upregulatory effect on eNOS mRNA expression and downregulatory effects on iNOS and 5-HT7 mRNA expression compared to the INDO group. However, antagonist (SB269970) administration did not result in such difference in gene expression, but even partially decreased the agonist’s effect in combination. Famotidine and agonist exerted similar effects. Histopathological findings supported the beneficial effects of 5-HT7 agonist on gastric tissue.
Conclusion
The study suggested that activation of 5-HT7 receptor showed a significant anti-ulcerogenic effect in the indomethacin-induced gastric ulcer model.
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Abbreviations
- AGO:
-
LP44 (5-HT7 agonist)
- ANTA:
-
SB-269970 (5-HT7 antagonist)
- COX-1:
-
Cyclooxygenase-1
- COX-2:
-
Cyclooxygenase-2
- DMSO:
-
Dimethyl sulfoxide
- ECs:
-
Enterochromaffin cells
- eNOS:
-
Endothelial nitric oxide synthase
- FAM:
-
Famotidine
- GIS:
-
Gastrointestinal system
- GMI:
-
Gastric microscopic injury
- GPCRs:
-
G-protein-coupled receptors
- GU:
-
Gastric ulcer
- H&E:
-
Hematoxylin–eosin
- HP:
-
Helicobacter pylori
- 5-HT:
-
5-Hydroxytryptamine
- 5-HT7 :
-
5-Hydroxytryptamine 7 receptor
- IL-1:
-
Interleukin-1
- INDO:
-
Indomethacin
- iNOS:
-
Inducible nitric oxide synthase
- MAO-A:
-
Monoamine oxidase A
- NO:
-
Nitric oxide
- NSAIDs:
-
Non-steroidal anti-inflammatory drugs
- PG:
-
Prostaglandin
- PGE2 :
-
Prostaglandin E2
- SD:
-
Standard deviation
- SERT:
-
Serotonin reuptake transporter
- TNFα:
-
Tumor necrosis factor alpha
References
Albayrak A et al (2013) Inflammation and peripheral 5-HT7 receptors: the role of 5-HT7 receptors in carrageenan induced inflammation in rats. Eur J Pharmacol 715:270–279. https://doi.org/10.1016/j.ejphar.2013.05.010
Arab HH, Salama SA, Omar HA, el Arafa SA, Maghrabi IA (2015) Diosmin protects against ethanol-induced gastric injury in rats: novel anti-ulcer actions. PLoS One 10:e0122417. https://doi.org/10.1371/journal.pone.0122417
Ayaz G, Halici Z, Albayrak A, Karakus E, Cadirci E (2017) Evaluation of 5-HT7 receptor trafficking on in vivo and in vitro model of lipopolysaccharide (LPS)-induced inflammatory cell injury in rats and LPS-treated A549. Cells Biochem Genet 55:34–47
Bard JA, Zgombick J, Adham N, Vaysse P, Branchek TA, Weinshank RL (1993) Cloning of a novel human serotonin receptor (5-HT7) positively linked to adenylate cyclase. J Biol Chem 268:23422–23426
Barrachina MD, Panes J, Esplugues JV (2001) Role of nitric oxide in gastrointestinal inflammatory and ulcerative diseases: perspective for drugs development. Curr Pharm Des 7:31–48
Biswas K, Bandyopadhyay U, Chattopadhyay I, Varadaraj A, Ali E, Banerjee RK (2003) A novel antioxidant and antiapoptotic role of omeprazole to block gastric ulcer through scavenging of hydroxyl radical. J Biol Chem 278:10993–11001
Bjerregaard H, Severinsen K, Said S, Wiborg O, Sinning S (2015) A dualistic conformational response to substrate binding in the human serotonin transporter reveals a high affinity state for serotonin. J Biol Chem 290:7747–7755. https://doi.org/10.1074/jbc.M114.573477
Bonaventure P, Nepomuceno D, Hein L, Sutcliffe JG, Lovenberg T, Hedlund PB (2004) Radioligand binding analysis of knockout mice reveals 5-hydroxytryptamine(7) receptor distribution and uncovers 8-hydroxy-2-(di-N-propylamino)tetralin interaction with alpha(2) adrenergic receptors. Neuroscience 124:901–911. https://doi.org/10.1016/j.neuroscience.2004.01.014
Brzozowski T, Konturek PC, Konturek SJ, Brzozowska I, Pawlik T (2005) Role of prostaglandins in gastroprotection and gastric adaptation. J Physiol Pharmacol 56(Suppl 5):33–55
Cadirci E et al (2013) Peripheral 5-HT7 receptors as a new target for prevention of lung injury and mortality in septic rats. Immunobiology 218:1271–1283. https://doi.org/10.1016/j.imbio.2013.04.012
Carbone C et al (2019) Prior activation of 5-HT7 receptors modulates the conditioned place preference with methylphenidate. Front Behav Neurosci 13:208. https://doi.org/10.3389/fnbeh.2019.00208
Carter D, Champney M, Hwang B, Eglen RM (1995) Characterization of a postjunctional 5-HT receptor mediating relaxation of guinea-pig isolated ileum. Eur J Pharmacol 280:243–250
Coates MD et al (2004) Molecular defects in mucosal serotonin content and decreased serotonin reuptake transporter in ulcerative colitis and irritable bowel syndrome. Gastroenterology 126:1657–1664
Crispino M, Volpicelli F, Perrone-Capano C (2020) Role of the serotonin receptor 7 in brain plasticity: from development to disease. Int J Mol Sci. https://doi.org/10.3390/ijms21020505
Debnath S, Guha D (2007) Role of Moringa oleifera on enterochromaffin cell count and serotonin content of experimental ulcer model. Indian J Exp Biol 45:726–731
Fang WF, Broughton A, Jacobson ED (1977) Indomethacin-induced intestinal inflammation. Am J Dig Dis 22:749–760. https://doi.org/10.1007/bf01694504
Fujisawa M, Murata T, Hori M, Ozaki H (2010) The 5-HT4 receptor agonist mosapride attenuates NSAID-induced gastric mucosal damage. J Gastroenterol 45:179–186. https://doi.org/10.1007/s00535-009-0170-3
Gidener S, Apaydin S, Kupelioglu A, Guven H, Gelal A, Gure A (1995) Serotonin causes acute gastric mucosal injury in rats, probably via 5HT1D receptors. Int J Exp Pathol 76:237–240
Gomaa AMS, Abd El-Mottaleb NA, Aamer HA (2018) Antioxidant and anti-inflammatory activities of alpha lipoic acid protect against indomethacin-induced gastric ulcer in rats. Biomed Pharmacother 101:188–194
Hoyer D et al (1994) International union of pharmacology classification of receptors for 5-hydroxytryptamine (serotonin). Pharmacol Rev 46:157–203
Hoyer D, Hannon JP, Martin GR (2002) Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554
Jin DC, Cao HL, Xu MQ, Wang SN, Wang YM, Yan F, Wang BM (2016) Regulation of the serotonin transporter in the pathogenesis of irritable bowel syndrome. World J Gastroenterol 22:8137–8148. https://doi.org/10.3748/wjg.v22.i36.8137
Kaplan KA et al (2012) Alpha-lipoic acid protects against indomethacin-induced gastric oxidative toxicity by modulating antioxidant system. J Food Sci 77:H224–230. https://doi.org/10.1111/j.1750-3841.2012.02920.x
Kato S et al (2012) Dual role of serotonin in the pathogenesis of indomethacin-induced small intestinal ulceration: pro-ulcerogenic action via 5-HT3 receptors and anti-ulcerogenic action via 5-HT4 receptors. Pharmacol Res 66:226–234. https://doi.org/10.1016/j.phrs.2012.06.002
Kim JJ, Khan WI (2014) 5-HT7 receptor signaling: improved therapeutic strategy in gut disorders. Front Behav Neurosci 8:396. https://doi.org/10.3389/fnbeh.2014.00396
Kim JJ et al (2013) Targeted inhibition of serotonin type 7 (5-HT7) receptor function modulates immune responses and reduces the severity of intestinal inflammation. J Immunol 190:4795–4804
Ligumsky M, Golanska EM, Hansen DG, Kauffman GL (1983) Aspirin can inhibit gastric-mucosal cyclo-oxygenase without causing lesions in rat. Gastroenterology 84:756–761
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Method Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262
Mathews CK, Van Holde KE (1990) Metabolism of nitrogenous compounds. Biochemistry. Benjamin/Cummings, Redwood, p 737–783
Nilsson T, Longmore J, Shaw D, Pantev E, Bard JA, Branchek T, Edvinsson L (1999) Characterisation of 5-HT receptors in human coronary arteries by molecular and pharmacological techniques. Eur J Pharmacol 372:49–56
Nishida K, Ohta Y, Ishiguro I (1997) Role of gastric mucosal constitutive and inducible nitric oxide synthases in the development of stress-induced gastric mucosal lesions in rats. Biochem Biophys Res Commun 236:275–279
Plassat JL, Amlaiky N, Hen R (1993) Molecular cloning of a mammalian serotonin receptor that activates adenylate cyclase. Mol Pharmacol 44:229–236
Podlewska S et al (2018) Structural insights into serotonin receptor ligands polypharmacology. Eur J Med Chem 151:797–814. https://doi.org/10.1016/j.ejmech.2018.04.010
Polat B, Halici Z, Cadirci E, Karakus E, Bayir Y, Albayrak A, Unal D (2017) Liver 5-HT7 receptors: a novel regulator target of fibrosis and inflammation-induced chronic liver injury in vivo and in vitro. Int Immunopharmacol 43:227–235. https://doi.org/10.1016/j.intimp.2016.12.023
Prins NH, Briejer MR, Van Bergen PJ, Akkermans LM, Schuurkes JA (1999) Evidence for 5-HT7 receptors mediating relaxation of human colonic circular smooth muscle. Br J Pharmacol 128:849–852. https://doi.org/10.1038/sj.bjp.0702762
Sanders-Bush EMS (2001) 5-Hydroxytryptamine (serotonin) receptor agonists and antagonists. In: Gilman G (ed) Goodman & Gilman’s the pharmacological basis of therapeutics, vol 10. McGraw Hill, USA, p 249–263
Satoh H, Inada I, Hirata T, Maki Y (1981) Indomethacin produces gastric antral ulcers in the refed rat. Gastroenterology 81:719–725
Soll A (1998) Peptic ulcer and its complications. In: Feldman M, Scharschmidt B (eds) Slesenger fordtrans gastrointestinal and hepatic disease: pathophisiology, diagnosis, management, 6th edn. Saunders, Philadelphia, pp 620–678
Suleyman H, Albayrak A, Bilici M, Cadirci E, Halici Z (2010) Different mechanisms in formation and prevention of indomethacin-induced gastric ulcers. Inflammation 33:224–234. https://doi.org/10.1007/s10753-009-9176-5
Tatar A, Yayla M, Kose D, Halici Z, Yoruk O, Polat E (2016) The role of endothelin-1 and endothelin receptor antagonists in allergic rhinitis inflammation: ovalbumin-induced rat model. Rhinology 54:266–272. https://doi.org/10.4193/Rhin15.059
Tonini M et al (2005) 5-HT7 receptors modulate peristalsis and accommodation in the guinea pig ileum. Gastroenterology 129:1557–1566. https://doi.org/10.1053/j.gastro.2005.08.005
Tuladhar BR, Ge L, Naylor RJ (2003) 5-HT7 receptors mediate the inhibitory effect of 5-HT on peristalsis in the isolated guinea-pig ileum. Br J Pharmacol 138:1210–1214. https://doi.org/10.1038/sj.bjp.0705184
Ullmer C, Schmuck K, Kalkman HO, Lubbert H (1995) Expression of serotonin receptor mRNAs in blood vessels. FEBS Lett 370:215–221
Wendelbo I, Mazzawi T, El-Salhy M (2014) Increased serotonin transporter immunoreactivity intensity in the ileum of patients with irritable bowel disease. Mol Med Rep 9:180–184. https://doi.org/10.3892/mmr.2013.1784
Whittle BJ, Lopez-Belmonte J, Moncada S (1990) Regulation of gastric mucosal integrity by endogenous nitric oxide: interactions with prostanoids and sensory neuropeptides in the rat. Br J Pharmacol 99:607–611
Xia Z et al (2018) Metabolic analysis of serotonin system in serum and gastric tissues of ovalbumin-induced allergic mice. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 34:320–326
Yayla M, Halici Z, Kose D, Tatar A, Sitki Gozeler M (2017) 5-HT7 receptors are over-expressed in patients with nasal polyps. Ear Nose Throat J 96:E14–E18
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Calik, I., Yayla, M., Cinar, I. et al. LP44 (4-[2-(methylthio)phenyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide) exerts anti-ulcer effects via 5-hydroxytryptamine receptor 7 activation on indomethacin-induced gastric ulcers in rats. Inflammopharmacol 28, 893–902 (2020). https://doi.org/10.1007/s10787-020-00725-3
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DOI: https://doi.org/10.1007/s10787-020-00725-3