The therapeutic potential of trifluoperazine against ethanol and cold water stress-induced gastric lesions in rat

Document Type : Original Article


1 Department of Pharmacology and Toxicology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran.

2 Food and Supplements Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

3 Medicinal Plants Processing, Shiraz University of Medical Sciences, Shiraz, Iran

4 Department of Medicinal Chemistry, Shiraz University of Medical Sciences, Shiraz, Iran.

5 Diagnostic Laboratory Sciences and Technology Research Center, School of Paramedical Sciences, Shiraz University of Medical Sciences, Shiraz, Iran


Gastric erosion is a multifactorial etiological disorder. The study aimed to evaluate the therapeutic effect of trifluoperazine (TFP ) on gastric lesioninduced by cold-water stress and ethanol in rats. TFP 5, 10 and 20 mg/kg as well as pantoprazole (20 mg/kg), as the standard treatment, was administered via oral gavage, 1 h before gastric lesion-induced by 50% ethanol (5 ml/kg per oral) or immersion in cold water (20-22 °C) in rats. Animals were anesthetized 1 h after ethanol gavage or 4 h after immersion in cold water. The stomach tissue was removed and allocated for histopathological and biochemical parameters including malondialdehyde (MDA )level, superoxide dismutase (SOD) and catalase (CAT) activity assay. Both models were induced significant increase in MDA level and decrease in SOD and CAT activity. Pre-treatment with TFP at doses of 10 and 20 mg/kg significantly increased the activity of SOD and CAT enzymes and decreased the concentration of MDA in both models. Also, pre-treatment with TFP ameliorated ethanol and cold-water stress-induced damage. TFP demonstrated gastric mucosal protection against oxidative injuries caused by ethanol and cold-water stress because of its antioxidant properties and inhibition of toxic oxidant in the stomach tissues.
Please cite this article as: Mohammad Javad Khoshnoud, Marzieh Rashedinia, Majid Keshavarzi, Amir Hosein Sakhteman, Vida Izadi, Amin Derakhshanfar. The therapeutic potential of trifluoperazine against ethanol and cold water stress-induced gastric lesions in rat. Trends in Pharmaceutical Sciences. 2022;8(1):13-24 .doi: 10.30476/TIPS.2021.92622.1112


1. Rodrigues Orsi P, Bonamin F, Aparecida Severi J, Cássia Santos R, Vilegas W, Hiruma-Lima CA, et al. Hymenaea stigonocarpa Mart. ex Hayne: a Brazilian medicinal plant with gastric and duodenal anti-ulcer and antidiarrheal effects in experimental rodent models. J Ethnopharmacol. 2012 Aug 30;143(1):81-90. doi: 10.1016/j.jep.2012.06.001. Epub 2012 Jun 27. PMID: 22750452.
2. Choudhary M, Kumar V, Singh S. Gastric antisecretory and cytoprotective effects of hydroalcoholic extracts of Plumeria alba Linn. leaves in rats. J Integr Med. 2014 Jan;12(1):42-51. doi: 10.1016/S2095-4964(14)60002-9. PMID: 24461594.
3. Popovic M, Janicijevic-Hudomal S, Kaurinovic B, Rasic J, Trivic S. Antioxidant effects of some drugs on ethanol-induced ulcers. Molecules. 2009 Feb 18;14(2):816-26. doi: 10.3390/molecules14020816. PMID: 19255541; PMCID: PMC6253987.
4. Hajrezaie M, Golbabapour S, Hassandarvish P, Gwaram NS, A Hadi AH, Mohd Ali H, et al. Acute toxicity and gastroprotection studies of a new schiff base derived copper (II) complex against ethanol-induced acute gastric lesions in rats. PLoS One. 2012;7(12):e51537. doi: 10.1371/journal.pone.0051537. Epub 2012 Dec 10. PMID: 23251568; PMCID: PMC3519725.
5. Devaraj VC, Krishna BG. Antiulcer activity of a polyherbal formulation (PHF) from Indian medicinal plants. Chin J Nat Med. 2013 Mar;11(2):145-8. doi: 10.1016/S1875-5364(13)60041-2. PMID: 23787181.
6. Saxena B, Krishnamurthy S, Singh S. Gastroprotective potential of risperidone, an atypical antipsychotic, against stress and pyloric ligation induced gastric lesions. Chem Biol Interact. 2011 Apr 25;190(2-3):155-64. doi: 10.1016/j.cbi.2011.02.002. Epub 2011 Feb 18. PMID: 21315700.
7. Saxena B, Singh S. Investigations on gastroprotective effect of citalopram, an antidepressant drug against stress and pyloric ligation induced ulcers. Pharmacol Rep. 2011;63(6):1413-26. doi: 10.1016/s1734-1140(11)70705-8. PMID: 22358089.
8. Tardy M, Dold M, Engel RR, Leucht S. Trifluoperazine versus low-potency first-generation antipsychotic drugs for schizophrenia. Cochrane Database Syst Rev. 2014 Jul 8;(7):CD009396. doi: 10.1002/14651858.CD009396.pub2. PMID: 25003310.
9. Liu S, Han Y, Zhang T, Yang Z. Protective effect of trifluoperazine on hydrogen peroxide-induced apoptosis in PC12 cells. Brain Res Bull. 2011 Feb 1;84(2):183-8. doi: 10.1016/j.brainresbull.2010.12.008. Epub 2010 Dec 21. PMID: 21172409.
10. Langmead L, Rampton DS. Review article: herbal treatment in gastrointestinal and liver disease--benefits and dangers. Aliment Pharmacol Ther. 2001 Sep;15(9):1239-52. doi: 10.1046/j.1365-2036.2001.01053.x.
11. Chaudhuri S, McCullough SS, Hennings L, Brown AT, Li SH, Simpson PM, et al Effect of trifluoperazine on toxicity, HIF-1α induction and hepatocyte regeneration in acetaminophen toxicity in mice. Toxicol Appl Pharmacol. 2012 Oct 15;264(2):192-201. doi: 10.1016/j.taap.2012.08.001. Epub 2012 Aug 10. PMID: 22902588; PMCID: PMC3519387.
12. Wen Y, Zhang Y, Li J, Luo F, Huang Z, Liu K. Low concentration trifluoperazine promotes proliferation and reduces calcium-dependent apoptosis in glioma cells. Sci Rep. 2018;8(1):1147.
13. Adinortey MB, Ansah C, Galyuon I, Nyarko A. In vivo models used for evaluation of potential antigastroduodenal ulcer agents. Ulcers. 2013;2013.
14. Umamaheswari M, Asokkumar K, Rathidevi R, Sivashanmugam AT, Subhadradevi V, Ravi TK. Antiulcer and in vitro antioxidant activities of Jasminum grandiflorum L. J Ethnopharmacol. 2007 Apr 4;110(3):464-70. doi: 10.1016/j.jep.2006.10.017. Epub 2006 Oct 21. PMID: 17125945.
15. Madesh M, Balasubramanian KA. A microtiter plate assay for superoxide using MTT reduction method. Indian J Biochem Biophys. 1997 Dec;34(6):535-9. PMID: 9594436.
16. Góth L. A simple method for determination of serum catalase activity and revision of reference range. Clin Chim Acta. 1991 Feb 15;196(2-3):143-51. doi: 10.1016/0009-8981(91)90067-m. PMID: 2029780.
17. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979 Jun;95(2):351-8. doi: 10.1016/0003-2697(79)90738-3. PMID: 36810.
18. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248-54. doi: 10.1006/abio.1976.9999. PMID: 942051.
19. Fernández de la Gandara F, Casas Carnicero J, Velasco Martin A. Effects of antidepressants on alcohol-induced gastric mucosal injury in rats. Methods Find Exp Clin Pharmacol. 1989 Oct;11(10):635-9. PMID: 2586196.
20. Gabry KE, Chrousos GP, Rice KC, Mostafa RM, Sternberg E, Negrao AB, et al. Marked suppression of gastric ulcerogenesis and intestinal responses to stress by a novel class of drugs. Mol Psychiatry. 2002;7(5):474-83, 433. doi: 10.1038/ PMID: 12082565.
21. Suleyman H, Cadirci E, Albayrak A, Polat B, Halici Z, Koc F, et al. Comparative study on the gastroprotective potential of some antidepressants in indomethacin-induced ulcer in rats. Chem Biol Interact. 2009 Jul 15;180(2):318-24. doi: 10.1016/j.cbi.2009.03.002. Epub 2009 Mar 14. PMID: 19497431.
22. Fornai M, Natale G, Colucci R, Tuccori M, Carazzina G, Antonioli L, et al. Mechanisms of protection by pantoprazole against NSAID-induced gastric mucosal damage. Naunyn Schmiedebergs Arch Pharmacol. 2005 Jul;372(1):79-87. doi: 10.1007/s00210-005-1075-1. Epub 2005 Aug 4. PMID: 16080005.
23. Shukla K, Raj P, Kumar A, Kumar M, Kaithwas G. Effect of monotherapy and combination therapy of pantoprazole and aprepitant in gastric esophageal reflux disease in albino rats. ScientificWorldJournal. 2014 Mar 23;2014:183147. doi: 10.1155/2014/183147. PMID: 24790551; PMCID: PMC3982274.
24. Engin S, Barut EN, Barut B, Kadioglu Duman M, Kaya C, Kerimoglu G, Ozel A. Uroprotective effect of pantoprazole against cyclophosphamide-induced cystitis in mice. Support Care Cancer. 2019 Nov;27(11):4273-4281. doi: 10.1007/s00520-019-04731-2. Epub 2019 Mar 14. PMID: 30874926.
25. Choudhary MK, Bodakhe SH, Gupta SK. Assessment of the antiulcer potential of Moringa oleifera root-bark extract in rats. J Acupunct Meridian Stud. 2013 Aug;6(4):214-20. doi: 10.1016/j.jams.2013.07.003. Epub 2013 Jul 27. PMID: 23972244.
26. Sahoo SK, Sahoo HB, Priyadarshini D, Soundarya G, Kumar CK, Rani KU. Antiulcer Activity of Ethanolic Extract of Salvadora indica (W.) Leaves on Albino Rats. J Clin Diagn Res. 2016 Sep;10(9):FF07-FF10. doi: 10.7860/JCDR/2016/20384.8470. Epub 2016 Sep 1. PMID: 27790462; PMCID: PMC5071962.
27. La Casa C, Villegas I, Alarcón de la Lastra C, Motilva V, Martín Calero MJ. Evidence for protective and antioxidant properties of rutin, a natural flavone, against ethanol induced gastric lesions. J Ethnopharmacol. 2000 Jul;71(1-2):45-53. doi: 10.1016/s0378-8741(99)00174-9. PMID: 10904145.
28. Rios ER, Rocha NF, Venâncio ET, Moura BA, Feitosa ML, Cerqueira GS, et al. Mechanisms involved in the gastroprotective activity of esculin on acute gastric lesions in mice. Chem Biol Interact. 2010 Oct 6;188(1):246-54. doi: 10.1016/j.cbi.2010.07.020. Epub 2010 Aug 1. PMID: 20678495.
29. Sowndhararajan K, Kang SC. Protective effect of ethyl acetate fraction of Acacia ferruginea DC. against ethanol-induced gastric ulcer in rats. J Ethnopharmacol. 2013 Jun 21;148(1):175-81. doi: 10.1016/j.jep.2013.04.007. Epub 2013 Apr 19. PMID: 23608239.
30. Boligon AA, de Freitas RB, de Brum TF, Waczuk EP, Klimaczewski CV, de Ávila DS, Athayde ML, de Freitas Bauermann L. Antiulcerogenic activity of Scutia buxifolia on gastric ulcers induced by ethanol in rats. Acta Pharm Sin B. 2014 Oct;4(5):358-67. doi: 10.1016/j.apsb.2014.05.001. Epub 2014 Jun 11. PMID: 26579405; PMCID: PMC4629092.
31. Laine L, Takeuchi K, Tarnawski A. Gastric mucosal defense and cytoprotection: bench to bedside. Gastroenterology. 2008 Jul;135(1):41-60. doi: 10.1053/j.gastro.2008.05.030. Epub 2008 Jun 10. PMID: 18549814.
32. Dekanski D, Janićijević-Hudomal S, Ristić S, Radonjić NV, Petronijević ND, Piperski V, Mitrović DM. Attenuation of cold restraint stress-induced gastric lesions by an olive leaf extract. Gen Physiol Biophys. 2009;28 Spec No:135-42. PMID: 19893091.
33. Dalla Libera A, Scutari G, Boscolo R, Rigobello MP, Bindoli A. Antioxidant properties of clozapine and related neuroleptics. Free Radic Res. 1998 Aug;29(2):151-7. doi: 10.1080/10715769800300171. PMID: 9790517.
34. Asghar MN, Khan IU. Measurement of antioxidant activity with trifluoperazine dihydrochloride radical cation. Braz J Med Biol Res. 2008 Jun;41(6):455-61. doi: 10.1590/s0100-879x2008000600003. PMID: 18622491.
35. Kuo KL, Liu SH, Lin WC, Hsu FS, Chow PM, Chang YW, Yang SP, Shi CS, Hsu CH, Liao SM, Chang HC. Trifluoperazine, an antipsychotic drug, effectively reduces drug resistance in cisplatin-resistant urothelial carcinoma cells via suppressing Bcl-xL: an in vitro and in vivo study. Int J Mol Sci. 2019 Jan;20(13):3218.
36. Souza dos Santos P, Saraiva DF, Ferraz da Costa DC, Scofano HM, de Carvalho-Alves PC. Trifluoperazine protects brain plasma membrane Ca(2+)-ATPase from oxidative damaging. Exp Brain Res. 2007 Mar;177(3):347-57. doi: 10.1007/s00221-006-0678-1. PMID: 16955267.
37. Kitagawa H, Fujiwara M, Osumi Y. Effects of water-immersion stress on gastric secretion and mucosal blood flow in rats. Gastroenterology. 1979 Aug;77(2):298-302. PMID: 447044.
38. Olaleye SB, Farombi EO. Attenuation of indomethacin- and HCl/ethanol-induced oxidative gastric mucosa damage in rats by kolaviron, a natural biflavonoid of Garcinia kola seed. Phytother Res. 2006 Jan;20(1):14-20. doi: 10.1002/ptr.1793. PMID: 16397915.
39. Govindarajan R, Vijayakumar M, Singh M, Rao ChV, Shirwaikar A, Rawat AK, et al. Antiulcer and antimicrobial activity of Anogeissus latifolia. J Ethnopharmacol. 2006 Jun 15;106(1):57-61. doi: 10.1016/j.jep.2005.12.002. Epub 2006 Jan 18. PMID: 16413714.
40. Brzozowski T, Konturek PC, Drozdowicz D, Konturek SJ, Zayachivska O, Pajdo R, et al. Grapefruit-seed extract attenuates ethanol-and stress-induced gastric lesions via activation of prostaglandin, nitric oxide and sensory nerve pathways. World J Gastroenterol. 2005 Nov 7;11(41):6450-8. doi: 10.3748/wjg.v11.i41.6450. PMID: 16425415; PMCID: PMC4355785.
41. Li Y, Yong DG, Geng BQ, Gu GG. [Antiulcer action and mechanism of trifluoperazine in rat stomach]. Zhongguo Yao Li Xue Bao. 1991 Sep;12(5):453-6. Chinese. PMID: 1819902.