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Tianeptine exerts ameliorative effects on acetic acid-induced colitis as detected by anti-inflammatory and antioxidant markers in rats; the role of anti-LOX and radical scavenging activity

Year 2025, Volume: 29 Issue: 3, 1017 - 1027, 04.06.2025

Dilek Özbeyli , Naziye Özkan Yenal , Meral Yüksel , Ali Şen , Aslı Aykaç

https://doi.org/10.12991/jrespharm.1694168

Abstract

Some patients with ulcerative colitis (UC) could benefit from antidepressant use, particularly when having concomitant depression or during the remission period. For this purpose, we investigated the therapeutic effects of Tianeptine (TT) on UC induced by acetic acid (AA) in rats from the perspective of both in vitro and in vivo antiinflammatory and antioxidant activity. Within the in vivo experiments, the rats were divided into control (C), AA+ TT, and AA+ sulfasalazine (AA+SS) groups. Colitis was induced with the application of AA 5% intrarectally. Compared to indomethacin (21.42 μg/ml), SS showed an equally strong anti-inflammatory activity (21.97 μg/ml), while Tianeptine had a good anti-LOX activity (88.57 μg/ml) in vitro. Compared to standard Trolox (13 μg/ml) against ABTS radical, Tianeptine (238.60 μg/ml) and sulfasalazine (1727 μg/ml) showed free radical scavenging activity in vitro. AA caused a depletion in colonic GSH (p<0.001) and an increase in MDA, MPO, luminol, and lucigenin chemiluminescence levels (p<0.01- p<0.001) compared with the C group. Macroscopic and microscopic scoring were elevated in the AA group (p<0.001). The AA+ TT and AA+ SS groups showed improvement in GSH, MDA, MPO, and CL levels compared to the AA group (p<0.01- p< 0.001). Macroscopic and microscopic scoring decreased in the AA+ TT and AA+ SS groups (p<0.001) compared to the AA group. In conclusion, our study demonstrated that TT has a curative effect on UC based on its in vitro and in vivo anti-inflammatory and antioxidant activities. TT can be used in patients with concomitant colon inflammation and depression.

Keywords

Ulcerative colitis Depression Tianeptine Anti-5-lipoxygenase Anti-ABTS MDA MPO GSH

References

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Year 2025, Volume: 29 Issue: 3, 1017 - 1027, 04.06.2025

Dilek Özbeyli , Naziye Özkan Yenal , Meral Yüksel , Ali Şen , Aslı Aykaç

https://doi.org/10.12991/jrespharm.1694168

Abstract

References

  • [1] Agrawal M, Jess T. Implications of the changing epidemiology of inflammatory bowel disease in a changing world. United Eur Gastroenterol J. 2022; 10(10): 1113–1120. https://doi.org/10.1002/ueg2.12317
  • [2] Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet. 2017; 389(10080): 1756-1770. https://doi.org/10.1016/S0140-6736(16)32126-2
  • [3] Bruner LP, White AM, Proksell S. Inflammatory Bowel Disease. Primary Care. 2023; 50(3): 411–427. https://doi.org/10.1016/j.pop.2023.03.009
  • [4] Chojnacki C, Walecka-Kapica E, Klupinska G, Pawłowicz M, Florkowski A, Wachowska-Kelly P, Chojnacki J. Ocena wpływu tianeptyny na stan psychosomatyczny [Evaluation of the influence of tianeptine on the psychosomatic status of patients with ulcerative colitis in remission]. Pol Merkur Lekarski. 2011; 31(182): 92-96.
  • [5] Jayasooriya N, Blackwell J, Saxena S, Bottle A, Petersen I, Creese H, Hotopf M, Pollok RCG; POP-IBD study group. Antidepressant medication use in Inflammatory Bowel Disease: a nationally representative population-based study. Aliment Pharmacol Ther. 2022; 55(10): 1330-1341. https://doi.org/10.1111/apt.16820.
  • [6] Olden KW. The use of antidepressants in functional gastrointestinal disorders: new uses for old drugs. CNS Spectr. 2005; 10(11): 891-896. https://doi.org/ 10.1017/s1092852900019866
  • [7] Kast RE. Anti- and pro-inflammatory considerations in antidepressant use during medical illness: bupropion lowers and mirtazapine increases circulating tumor necrosis factor-alpha levels. Gen Hosp Psychiatry. 2003; 25(6): 495–496. https://doi.org/ 10.1016/s0163-8343(03)00093-8.
  • [8] Gracie DJ, Guthrie EA, Hamlin PJ, Ford AC. Bi-directionality of brain-gut interactions in patients with inflammatory bowel disease. Gastroenterology. 2018; 154(6): 1635-1646.e3. https://doi.org/ 10.1053/j.gastro.2018.01.027
  • [9] Sohn W, Lee OY, Kwon JG, Park KS, Lim YJ, Kim TH, Jung SW, Kim JI. Tianeptine vs amitriptyline for the treatment of irritable bowel syndrome with diarrhea: A multicenter, open-label, non-inferiority, randomized controlled study. Neurogastroenterol Motil. 2012; 24(9): 860-e398. https://doi.org/ 10.1111/j.1365-2982.2012.01945.x
  • [10] McEwen BS, Chattarji S, Diamond DM, Jay TM, Reagan LP, Svenningsson P, Fuchs E. The neurobiological properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation. Mol Psychiatry. 2010; 15(3): 237-249. https://doi.org/ 10.1038/mp.2009.80
  • [11] Wang J, Li L, Chen P, He C, Niu X, Mei Q. Homocysteine aggravates intestinal inflammation through promotion of 5-LOX and COX-2 in IBD. Eur J Med Res. 2024; 29(1): 537. https://doi.org/10.1186/s40001-024-02125-7
  • [12] Cuzzocrea S, Rossi A, Mazzon E, Di Paola R, Genovese T, Muià C, Caputi AP, Sautebin L. 5-Lipoxygenase modulates colitis through the regulation of adhesion molecule expression and neutrophil migration. Lab Invest. 2005; 85(6): 808-822. https://doi.org/10.1038/labinvest.3700276
  • [13] Reeta Kh, Prabhakar P, Gupta YK. Anticonvulsant activity of the antidepressant drug, tianeptine, against pentylenetetrazole-induced seizures mitigates cognitive impairment in rats. Behav Pharmacol. 2016; 27(7): 623-632. https://doi.org/ 10.1097/FBP.0000000000000257
  • [14] Suleyman H, Cadirci E, Albayrak A, Polat B, Halici Z, Koc F, Hacimuftuoglu A, Bayir Y. Comparative study on the gastroprotective potential of some antidepressants in indomethacin-induced ulcer in rats. Chem Biol Interact. 2009; 180(2): 318-324. https://doi.org/ 10.1016/j.cbi.2009.03.002
  • [15] Koc F, Karakus E, Ragbetli C, Çetin N, Kırbaş A. Direct Role of α 2 -Adrenoreceptors in Antiulcer Effect Mechanism of Tianeptine in Rats. Kafkas Üniv Vet Fak Derg. 2012 (18): 713-718. https://doi.org/ 10.9775/kvfd.2011.5950
  • [16] Rådmark O, Werz O, Steinhilber D, Samuelsson B. 5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease. Biochim Biophys Acta. 2015; 1851(4): 331-339. https://doi.org/10.1016/j.bbalip.2014.08.012
  • [17] Kahnt AS, Angioni C, Göbel T, Hofmann B, Roos J, Steinbrink SD, Rörsch F, Thomas D, Geisslinger G, Zacharowski K, Grösch S, Steinhilber D, Maier TJ. Inhibitors of Human 5-Lipoxygenase Potently Interfere With Prostaglandin Transport. Front Pharmacol. 2022; 12: 782584. https://doi.org/10.3389/fphar.2021.782584
  • [18] Eshwarappa RS, Ramachandra YL, Subaramaihha SR, Subbaiah SG, Austin RS, Dhananjaya BL. Anti-Lipoxygenase Activity of Leaf Gall Extracts of Terminalia chebula (Gaertn.) Retz. (Combretaceae). Pharmacognosy Res. 2016; 8(1): 78-82. https://doi.org/ 10.4103/0974-8490.171103
  • [19] Wallace JL, Keenan CM, Gale D, Shoupe TS. Exacerbation of experimental colitis by nonsteroidal anti-inflammatory drugs is not related to elevated leukotriene B4 synthesis. Gastroenterology. 1992; 102(1): 18-27. https://doi.org/ 10.1016/0016-5085(92)91779-4
  • [20] Olszowy M, Dawidowicz AL. Is it possible to use the DPPH and ABTS methods for reliable estimation of antioxidant power of colored compounds? Chem Pap. 2018; 72: 393–400. https://doi.org/ 10.1007/s11696-017-0288-3
  • [21] Re R, Pellegrini N, Proteggente A, Pannala A, Yang M, Rice-Evans C. Antioxidant activity applying an improved ABTS radical cation decolorization assay. Free Radic Biol Med. 1999; 26(9-10): 1231-1237. https://doi.org/ 10.1016/s0891-5849(98)00315-3
  • [22] Hussain R, Rehman W, Khan S, Maalik A, Hefnawy M, Alanazi AS, Khan Y, Rasheed L. Discovery of imidazopyridine derived oxadiazole-based thiourea derivatives as potential anti-diabetic agents: Synthesis, in vitro antioxidant screening and in silico molecular modeling approaches. J Mol Struc. 2023; 1293: 136185. https://doi.org/ 10.1016/j.molstruc.2023.136185
  • [23] Pearson DC, Jourd'heuil D, Meddings JB. The anti-oxidant properties of 5-aminosalicylic acid. Free Radic Biol Med. 1996; 21(3): 367-373. https://doi.org/10.1016/0891-5849(96)00031-7
  • [24] Randhawa PK, Singh K, Singh N, Jaggi AS. A review on chemical-induced inflammatory bowel disease models in rodents. Korean J Physiol Pharmacol. 2014; 18(4): 279-288. https://doi.org/ 10.4196/kjpp.2014.18.4.279
  • [25] El-Akabawy G, El-Sherif NM. Zeaxanthin exerts protective effects on acetic acid-induced colitis in rats via modulation of pro-inflammatory cytokines and oxidative stress. Biomed Pharmacother. 2019; 111: 841-851. https://doi.org/10.1016/j.biopha.2019.01.001
  • [26] Otu-Boakye SA, Yeboah KO, Boakye-Gyasi E, Oppong-Kyekyeku J, Okyere PD, Osafo N. Acetic acid-induced colitis modulating potential of total crude alkaloidal extract of Picralima nitida seeds in rats. Immun Inflamm Dis. 2023; 11(5): e855. https://doi.org/ 10.1002/iid3.855.
  • [27] Küpeli Akkol E, Gürağaç Dereli FT, Taştan H, Sobarzo-Sánchez E, Khan H. Effect of Sorbus domestica and its active constituents in an experimental model of colitis rats induced by acetic acid. J Ethnopharmacol. 2020; 251: 112521. https://doi.org/ 10.1016/j.jep.2019.112521
  • [28] Della FP, Abelaira HM, Réus GZ, Antunes AR, Dos Santos MA, Zappelinni G, Steckert AV, Vuolo F, Galant LS, Dal-Pizzol F, Kapczinski F, Quevedo J. Tianeptine exerts neuroprotective effects in the brain tissue of rats exposed to the chronic stress model. Pharmacol Biochem Behav. 2012; 103(2): 395-402. https://doi.org/ 10.1016/j.pbb.2012.09.018
  • [29] Süleyman B, Özbek Bilgin A, Mammadov R. Tianeptinin sıçanlarda iskemi reperfüzyonla oluşturulan oksidatif böbrek hasarına etkisi. Erzincan Univ J Sci Tech. 2018; 11: 300-305. https://doi.org/ 10.18185/erzifbed.422543
  • [30] Yıldız S, Uğur K, Taş HG, Özçiçek F, Kuyrukluyıldız U, Mendil AS, Çankaya M, Mammadov R, Süleyman H. Molecular mechanism of the protective effect of tianeptine against ketamine-induced cardiac injury in rats. Acta Farm Bonaer. 2021;40 (12): 2920-2926.
  • [31] Gassaway MM, Rives ML, Kruegel AC, Javitch JA, Sames D. The atypical antidepressant and neurorestorative agent tianeptine is a μ-opioid receptor agonist. Transl Psychiatry. 2014; 4(7): e411. https://doi.org/ 10.1038/tp.2014.30
  • [32] Collins S, Verma-Gandhu M. The putative role of endogenous and exogenous opiates in inflammatory bowel disease. Gut. 2006; 55(6): 756-757. https://doi.org/ 10.1136/gut.2005.084418.
  • [33] Philippe D, Chakass D, Thuru X, Zerbib P, Tsicopoulos A, Geboes K, Bulois P, Breisse M, Vorng H, Gay J, Colombel JF, Desreumaux P, Chamaillard M. Mu opioid receptor expression is increased in inflammatory bowel diseases: Implications for homeostatic intestinal inflammation. Gut. 2006; 55(6): 815-823. https://doi.org/ 10.1136/gut.2005.080887.
  • [34] Eisenstein TK, Hilburger ME. Opioid modulation of immune responses: effects on phagocyte and lymphoid cell populations. J Neuroimmunol. 1998(1-2); 83: 36-44. https://doi.org/ 10.1016/s0165-5728(97)00219-1
  • [35] Yıldırım A, Şen A, Doğan A, Bitis L. Antioxidant and anti-inflammatory activity of capitula, leaf and stem extracts of Tanacetum cilicicum (Boiss.) Grierson. Int J Second Metab. 2019; 6(2): 211-222. https://doi.org/ 10.21448/ijsm.510316
  • [36] Han SM, Kim YH, Jo HU, Kwak JA, Park HJ. Tianeptine reduces mechanical allodynia in spinal nerve-ligated and chemotherapy-induced neuropathic mice. Pain Physician. 2017; 20(4): E593–E600.
  • [37] Sakthivel KM, Guruvayoorappan C. Modulating effect of Biophytum sensitivum extract on rats with acetic acid-induced ulcerative colitis. Pharm Biol. 2014; 52(12): 1570-1580. https://doi.org/ 10.3109/13880209.2014.908396
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  • [39] Iseri SO, Ersoy Y, Ercan F, Yuksel M, Atukeren P, Gumustas K, Alican I. The effect of sildenafil, a phosphodiesterase-5 inhibitor, on acetic acid-induced colonic inflammation in the rat. J Gastroenterol Hepatol. 2009; 24(6): 1142–1148. https://doi.org/10.1111/j.1440-1746.2009.05797.x
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There are 44 citations in total.

Details

Primary Language English
Subjects Pharmacology and Pharmaceutical Sciences (Other)
Journal Section Articles
Authors

Dilek Özbeyli

Naziye Özkan Yenal

Meral Yüksel

Ali Şen

Aslı Aykaç

Publication Date June 4, 2025
Submission Date October 28, 2024
Acceptance Date January 11, 2025
Published in Issue Year 2025 Volume: 29 Issue: 3

Cite

APA Özbeyli, D., Özkan Yenal, N., Yüksel, M., Şen, A., et al. (2025). Tianeptine exerts ameliorative effects on acetic acid-induced colitis as detected by anti-inflammatory and antioxidant markers in rats; the role of anti-LOX and radical scavenging activity. Journal of Research in Pharmacy, 29(3), 1017-1027. https://doi.org/10.12991/jrespharm.1694168
AMA Özbeyli D, Özkan Yenal N, Yüksel M, Şen A, Aykaç A. Tianeptine exerts ameliorative effects on acetic acid-induced colitis as detected by anti-inflammatory and antioxidant markers in rats; the role of anti-LOX and radical scavenging activity. J. Res. Pharm. June 2025;29(3):1017-1027. doi:10.12991/jrespharm.1694168
Chicago Özbeyli, Dilek, Naziye Özkan Yenal, Meral Yüksel, Ali Şen, and Aslı Aykaç. “Tianeptine Exerts Ameliorative Effects on Acetic Acid-Induced Colitis As Detected by Anti-Inflammatory and Antioxidant Markers in Rats; The Role of Anti-LOX and Radical Scavenging Activity”. Journal of Research in Pharmacy 29, no. 3 (June 2025): 1017-27. https://doi.org/10.12991/jrespharm.1694168.
EndNote Özbeyli D, Özkan Yenal N, Yüksel M, Şen A, Aykaç A (June 1, 2025) Tianeptine exerts ameliorative effects on acetic acid-induced colitis as detected by anti-inflammatory and antioxidant markers in rats; the role of anti-LOX and radical scavenging activity. Journal of Research in Pharmacy 29 3 1017–1027.
IEEE D. Özbeyli, N. Özkan Yenal, M. Yüksel, A. Şen, and A. Aykaç, “Tianeptine exerts ameliorative effects on acetic acid-induced colitis as detected by anti-inflammatory and antioxidant markers in rats; the role of anti-LOX and radical scavenging activity”, J. Res. Pharm., vol. 29, no. 3, pp. 1017–1027, 2025, doi: 10.12991/jrespharm.1694168.
ISNAD Özbeyli, Dilek et al. “Tianeptine Exerts Ameliorative Effects on Acetic Acid-Induced Colitis As Detected by Anti-Inflammatory and Antioxidant Markers in Rats; The Role of Anti-LOX and Radical Scavenging Activity”. Journal of Research in Pharmacy 29/3 (June 2025), 1017-1027. https://doi.org/10.12991/jrespharm.1694168.
JAMA Özbeyli D, Özkan Yenal N, Yüksel M, Şen A, Aykaç A. Tianeptine exerts ameliorative effects on acetic acid-induced colitis as detected by anti-inflammatory and antioxidant markers in rats; the role of anti-LOX and radical scavenging activity. J. Res. Pharm. 2025;29:1017–1027.
MLA Özbeyli, Dilek et al. “Tianeptine Exerts Ameliorative Effects on Acetic Acid-Induced Colitis As Detected by Anti-Inflammatory and Antioxidant Markers in Rats; The Role of Anti-LOX and Radical Scavenging Activity”. Journal of Research in Pharmacy, vol. 29, no. 3, 2025, pp. 1017-2, doi:10.12991/jrespharm.1694168.
Vancouver Özbeyli D, Özkan Yenal N, Yüksel M, Şen A, Aykaç A. Tianeptine exerts ameliorative effects on acetic acid-induced colitis as detected by anti-inflammatory and antioxidant markers in rats; the role of anti-LOX and radical scavenging activity. J. Res. Pharm. 2025;29(3):1017-2.