Exploring the therapeutic potential of Long pepper (Piper longum) in stress management and ulcer prevention in zebrafish

Deepti Barla; Abirami Gopalakrishnan; Jayanthi Malaiyandi; Ashok Kumar Krishna Kumar; Ronald Darwin Chellappan; Kumar Krishnan; Ranjithkumar Murugesan; Senthilkumar Palanisamy; Suganthi Muthusamy

doi:10.7324/JAPS.2025.224111

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Abstract

Long pepper (Piper longum), traditionally recognized for its medicinal properties, including anti-inflammatory, antioxidant, immunomodulatory, neuroprotective, and digestive aid effects, also valued in Ayurvedic practices for antiulcer benefits. Methanol extraction was used to obtain a purified crude extract, which was then assessed for its antioxidant and anti-inflammatory activities. Ulcers were induced in zebrafish using dextran sodium sulfate over a 7-day period, followed by a 7-day treatment phase with fish feed mixed with P. longum extract. On the 21st day, zebrafish were analyzed through specific biochemical assays, including total protein concentration, lipid peroxidation, lactate dehydrogenase, and glutathione peroxidase to assess antioxidant and inflammatory markers, along with histological examination of intestinal tissue. Histological analysis revealed a reduction in ulcer size and number in the treatment group, with signs of healing including epithelial regeneration, decreased inflammatory cell infiltration, and tissue remodeling, contributing to the restoration of normal mucosal structure. Overall, these findings suggest that P. longum offers potential therapeutic effects against gastric ulcers and holds promise for managing stress, supporting its traditional uses as a natural therapeutic agent.

Keyword: Piper longum ulcer prevention therapeutic effects gastric ulcers human disease

Citation:

Barla D, Gopalakrishnan A, Malaiyandi J, Kumar AKK, Chellappan RD, Krishnan K, Murugesan R, Palanisamy S, Suganthi Muthusamy S. Exploring the therapeutic potential of Long pepper (Piper longum) in stress management and ulcer prevention in zebra fish. J Appl Pharm Sci. 2025. Online First. http://doi.org/10.7324/JAPS.2025.224111

Copyright: © The Author(s). This is an open-access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Reference

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2. Sharifi-Rad M, Fokou PVT, Sharopov F, Martorell M, Ademiluyi AO, Rajkovic J, et al. Antiulcer agents: from plant extracts to phytochemicals in healing promotion. Molecules. 2018;23(7):1751. https://doi.org/10.3390/molecules23071751
3. Derosa G, Maffioli P, Sahebkar A. Piperine and its role in chronic diseases. Adv Exp Med Biol. 2016:928:173-184. https://doi.org/10.1007/978-3-319-41334-1_8
4. Jaiswal F, Rai AK, Wal P, Wal A, Singh SP. Peptic ulcer: a review on etiology, pathogenesis, and treatment. Asian J Pharm Educ Res. 2021;10(4):1. https://doi.org/10.38164/AJPER/10.4.2021.1-17
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6. Fluckiger FA, Hanbury D. Pharmacographia: a history of the principal drugs of vegetable origin met with in Great Britain and British India. London: Macmillan; 1890. 1889-93 pp.
7. Binti Raja Idris RI, Mohd Taufek N, Nordin NO, Al-Saari N. Zebrafish nutrition: promoting fish health and welfare of the animal model in halal science research. Halalsphere. 2022;2:106-21. https://doi.org/10.31436/hs.v2i1.40
8. Teame T, Zhang Z, Ran C, Zhang H, Yang Y, Ding Q, et al. The use of zebrafish (Danio rerio) as biomedical models. Anim Front. 2019;9(3):68-77. https://doi.org/10.1093/af/vfz020
9. Eichele DD, Kharbanda KK. Dextran sodium sulfate colitis murine model: an indispensable tool for advancing our understanding of inflammatory bowel disease pathogenesis. World J Gastroenterol. 2017;23(33):6016-29. https://doi.org/10.3748/wjg.v23.i33.6016
10. Jamwal S, Kumar P. Animal models of inflammatory bowel disease. In: Michael Conn P, editor. Animal models for the study of human disease. 2nd ed. Academic Press; 2017. pp 467-77. https://doi.org/10.1016/B978-0-12-809468-6.00019-X
11. Agrawal AK, Rao C, Joshi V, Goel R. Effect of Piper longum Linn, Zingiber officinale Linn, and Ferula species on gastric ulceration and secretion in rats. Indian J Exp Biol. 2000;38:994-8.
12. Nadkarni KM. Indian materia medica. Vol 1. Mumbai: Popular Prakashan; 1976. 805-7 pp.
13. Katalinic V, Milos M, Modun D, Majek P, Brcic M. The DPPH free radical scavenging activity of some herbs and spices. Food Chem. 2006;94(4):558-64.
14. Benzie IF, Strain JJ. Ferric reducing/antioxidant power assay: direct measure of total antioxidant activity of biological fluids and modified version for simultaneous measurement of total antioxidant power and ascorbic acid concentration. Methods Enzymol. 1996;299:15-27. https://doi.org/10.1016/S0076-6879(99)99005-5
15. Mizushima Y, Kobayashi M. Interaction of anti-inflammatory drugs with serum proteins, especially with some biologically active proteins. J Pharm Pharmacol. 1968;20(3):169-73. https://doi.org/10.1111/j.2042-7158.1968.tb09718.x
16. Shinde UA, Phadke AS, Nair AM, Mungantiwar AA, Dikshit VJ, Saraf MN. Membrane stabilizing activity: a possible mechanism of action for the anti-inflammatory activity of Cedrus deodara wood oil. Fitoterapia. 1999;70(3):251-7. https://doi.org/10.1016/S0367-326X(99)00030-1
17. Wirtz S, Popp V, Kindermann M, Gerlach K, Weigmann B, Fichtner-Feigl S, et al. Chemically induced mouse models of acute and chronic intestinal inflammation. Nat Protoc. 2017;12:1295-309. https://doi.org/10.1038/nprot.2017.044
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;72(1-2):248-54. https://doi.org/10.1006/abio.1976.9999
19. Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide. 2001;5(1):62-71. https://doi.org/10.1006/niox.2000.0319
20. Tamagno WA, Alves C, Tessaro D, Sutorillo NT, Santin W, Barcellos LJG. Deferoxamine supplementation abolished iron-related toxicity of Ilex paraguariensis extract: behavioral and biochemical evaluation in adult zebrafish (Danio rerio). Antioxidants (Basel). 2022 Jul 31;11(8):1507. https://doi.org/10.3390/antiox11081507
21. Marklund S, Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem. 1974;47(3):469-74. https://doi.org/10.1111/j.1432-1033.1974.tb03714.x
22. Aebi H. Catalase in vitro. Methods Enzymol. 1984;105:121-6. https://doi.org/10.1016/S0076-6879(84)05016-3
23. Flohe L, Gunzler WA. Assays of glutathione peroxidase. Methods Enzymol. 1984;105:114-21. https://doi.org/10.1016/S0076-6879(84)05015-1
24. Zaveri S, Iyer R, Chaturvedi R. Pharmacological properties of Piper longum. Phytother Res. 2020;34(1):12-23.
25. Sarkar A, Sharma P, Khan S. Integrated pest management strategies for fruit fly control: an overview. J Agric Sci. 2017;15(3):123-30.
26. Kotha RR, Tareq FS, Yildiz E, Luthria DL. Oxidative stress and antioxidants-a critical review on in vitro antioxidant assays. Antioxidants (Basel). 2022;11(12):2388. https://doi.org/10.3390/antiox11122388
27. Valgimigli L. Lipid peroxidation and antioxidant protection. Biomolecules. 2023;13(9):1291. https://doi.org/10.3390/biom13091291
28. Palacios-Espinosa JF, Arroyo-García O, García-Valencia G, Linares E, Bye R, Romero I. Evidence of the anti-Helicobacter pylori, gastroprotective, and anti-inflammatory activities of Cuphea aequipetala infusion. J Ethnopharmacol. 2014;15:990-8. https://doi.org/10.1016/j.jep.2013.12.012
29. Sagradas J, Costa G, Figueirinha A, Castel-Branco MM, Silvério Cabrita AM, Figueiredo IV, et al. Gastroprotective effect of Cymbopogon citratus infusion on acute ethanol-induced gastric lesions in rats. J Ethnopharmacol. 2015;173:134-8. https://doi.org/10.1016/j.jep.2015.07.001
30. Chandra P, Kishore K, Ghosh AK. Assessment of antisecretory, gastroprotective, and in vitro antacid potential of Daucus carota in experimental rats. Osong Public Health Res Perspect. 2015;6:329-35. https://doi.org/10.1016/j.phrp.2015.10.006
31. Han H, Gao M, Wang F. Protective effects of patchouli alcohol against DSS-induced ulcerative colitis. Sci Rep. 2024;14:16745. https://doi.org/10.1038/s41598-024-66259-8
32. Lopez Nadal A, Boekhorst J, Lute C, van den Berg F, Schorn MA, Bergen Eriksen T, et al. Omics and imaging combinatorial approach reveals butyrate-induced inflammatory effects in the zebrafish gut. Anim Microbiome. 2023;5:15. https://doi.org/10.1186/s42523-023-00230-2
33. Yadav V, Chatterjee SS, Majeed M, Kumar V. Long-lasting preventive effects of piperlongumine and a Piper longum extract against stress-triggered pathologies in mice. J Intercult Ethnopharmacol. 2015;4(4):277-83. https://doi.org/10.5455/jice.20150921010411
34. Azeez TB, Lunghar J. 5 - Antiinflammatory effects of turmeric (Curcuma longa) and ginger (Zingiber officinale). In: Gopi S, Amalraj A, Kunnumakkara A, Thomas S, editors. Inflammation and natural products. London, UK: Academic Press; 2021. pp. 83-102. https://doi.org/10.1016/B978-0-12-819218-4.00011-0
35. Selvaraj LK, Jeyabalan S, Wong LS, Sekar M, Logeshwari B, Umamaheswari S. Baicalein prevents stress-induced anxiety behaviors in zebrafish model. Front Pharmaco. 2022;13:990799. https://doi.org/10.3389/fphar.2022.990799

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Gopalakrishnan A [PubMed] [Google Scholar ]

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Kumar A K K [PubMed] [Google Scholar ]

Chellappan R D [PubMed] [Google Scholar ]

Krishnan K [PubMed] [Google Scholar ]

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By article title

1. Vimala G, Shoba F. A review on antiulcer activity of few Indian medicinal plants. Int J Microbiol. 2014;2014:519590. https://doi.org/10.1155/2014/519590

2. Sharifi-Rad M, Fokou PVT, Sharopov F, Martorell M, Ademiluyi AO, Rajkovic J, et al. Antiulcer agents: from plant extracts to phytochemicals in healing promotion. Molecules. 2018;23(7):1751. https://doi.org/10.3390/molecules23071751

3. Derosa G, Maffioli P, Sahebkar A. Piperine and its role in chronic diseases. Adv Exp Med Biol. 2016:928:173-184. https://doi.org/10.1007/978-3-319-41334-1_8

4. Jaiswal F, Rai AK, Wal P, Wal A, Singh SP. Peptic ulcer: a review on etiology, pathogenesis, and treatment. Asian J Pharm Educ Res. 2021;10(4):1. https://doi.org/10.38164/AJPER/10.4.2021.1-17

5. Biswas P, Ghorai M, Mishra T, Gopalakrishnan AV, Roy D, Mane AB, et al. Piper longum L. A comprehensive review on traditional uses, phytochemistry, pharmacology, and health-promoting activities. Phytother Res. 2022;36(12):4425-76. https://doi.org/10.1002/ptr.7649

6. Fluckiger FA, Hanbury D. Pharmacographia: a history of the principal drugs of vegetable origin met with in Great Britain and British India. London: Macmillan; 1890. 1889-93 pp.

7. Binti Raja Idris RI, Mohd Taufek N, Nordin NO, Al-Saari N. Zebrafish nutrition: promoting fish health and welfare of the animal model in halal science research. Halalsphere. 2022;2:106-21. https://doi.org/10.31436/hs.v2i1.40

8. Teame T, Zhang Z, Ran C, Zhang H, Yang Y, Ding Q, et al. The use of zebrafish (Danio rerio) as biomedical models. Anim Front. 2019;9(3):68-77. https://doi.org/10.1093/af/vfz020

9. Eichele DD, Kharbanda KK. Dextran sodium sulfate colitis murine model: an indispensable tool for advancing our understanding of inflammatory bowel disease pathogenesis. World J Gastroenterol. 2017;23(33):6016-29. https://doi.org/10.3748/wjg.v23.i33.6016

10. Jamwal S, Kumar P. Animal models of inflammatory bowel disease. In: Michael Conn P, editor. Animal models for the study of human disease. 2nd ed. Academic Press; 2017. pp 467-77. https://doi.org/10.1016/B978-0-12-809468-6.00019-X

11. Agrawal AK, Rao C, Joshi V, Goel R. Effect of Piper longum Linn, Zingiber officinale Linn, and Ferula species on gastric ulceration and secretion in rats. Indian J Exp Biol. 2000;38:994-8.

12. Nadkarni KM. Indian materia medica. Vol 1. Mumbai: Popular Prakashan; 1976. 805-7 pp.

13. Katalinic V, Milos M, Modun D, Majek P, Brcic M. The DPPH free radical scavenging activity of some herbs and spices. Food Chem. 2006;94(4):558-64.

14. Benzie IF, Strain JJ. Ferric reducing/antioxidant power assay: direct measure of total antioxidant activity of biological fluids and modified version for simultaneous measurement of total antioxidant power and ascorbic acid concentration. Methods Enzymol. 1996;299:15-27. https://doi.org/10.1016/S0076-6879(99)99005-5

15. Mizushima Y, Kobayashi M. Interaction of anti-inflammatory drugs with serum proteins, especially with some biologically active proteins. J Pharm Pharmacol. 1968;20(3):169-73. https://doi.org/10.1111/j.2042-7158.1968.tb09718.x

16. Shinde UA, Phadke AS, Nair AM, Mungantiwar AA, Dikshit VJ, Saraf MN. Membrane stabilizing activity: a possible mechanism of action for the anti-inflammatory activity of Cedrus deodara wood oil. Fitoterapia. 1999;70(3):251-7. https://doi.org/10.1016/S0367-326X(99)00030-1

17. Wirtz S, Popp V, Kindermann M, Gerlach K, Weigmann B, Fichtner-Feigl S, et al. Chemically induced mouse models of acute and chronic intestinal inflammation. Nat Protoc. 2017;12:1295-309. https://doi.org/10.1038/nprot.2017.044

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;72(1-2):248-54. https://doi.org/10.1006/abio.1976.9999

19. Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide. 2001;5(1):62-71. https://doi.org/10.1006/niox.2000.0319

20. Tamagno WA, Alves C, Tessaro D, Sutorillo NT, Santin W, Barcellos LJG. Deferoxamine supplementation abolished iron-related toxicity of Ilex paraguariensis extract: behavioral and biochemical evaluation in adult zebrafish (Danio rerio). Antioxidants (Basel). 2022 Jul 31;11(8):1507. https://doi.org/10.3390/antiox11081507

21. Marklund S, Marklund G. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem. 1974;47(3):469-74. https://doi.org/10.1111/j.1432-1033.1974.tb03714.x

22. Aebi H. Catalase in vitro. Methods Enzymol. 1984;105:121-6. https://doi.org/10.1016/S0076-6879(84)05016-3

23. Flohe L, Gunzler WA. Assays of glutathione peroxidase. Methods Enzymol. 1984;105:114-21. https://doi.org/10.1016/S0076-6879(84)05015-1

24. Zaveri S, Iyer R, Chaturvedi R. Pharmacological properties of Piper longum. Phytother Res. 2020;34(1):12-23.

25. Sarkar A, Sharma P, Khan S. Integrated pest management strategies for fruit fly control: an overview. J Agric Sci. 2017;15(3):123-30.

26. Kotha RR, Tareq FS, Yildiz E, Luthria DL. Oxidative stress and antioxidants-a critical review on in vitro antioxidant assays. Antioxidants (Basel). 2022;11(12):2388. https://doi.org/10.3390/antiox11122388

27. Valgimigli L. Lipid peroxidation and antioxidant protection. Biomolecules. 2023;13(9):1291. https://doi.org/10.3390/biom13091291

28. Palacios-Espinosa JF, Arroyo-García O, García-Valencia G, Linares E, Bye R, Romero I. Evidence of the anti-Helicobacter pylori, gastroprotective, and anti-inflammatory activities of Cuphea aequipetala infusion. J Ethnopharmacol. 2014;15:990-8. https://doi.org/10.1016/j.jep.2013.12.012

29. Sagradas J, Costa G, Figueirinha A, Castel-Branco MM, Silvério Cabrita AM, Figueiredo IV, et al. Gastroprotective effect of Cymbopogon citratus infusion on acute ethanol-induced gastric lesions in rats. J Ethnopharmacol. 2015;173:134-8. https://doi.org/10.1016/j.jep.2015.07.001

30. Chandra P, Kishore K, Ghosh AK. Assessment of antisecretory, gastroprotective, and in vitro antacid potential of Daucus carota in experimental rats. Osong Public Health Res Perspect. 2015;6:329-35. https://doi.org/10.1016/j.phrp.2015.10.006

31. Han H, Gao M, Wang F. Protective effects of patchouli alcohol against DSS-induced ulcerative colitis. Sci Rep. 2024;14:16745. https://doi.org/10.1038/s41598-024-66259-8

32. Lopez Nadal A, Boekhorst J, Lute C, van den Berg F, Schorn MA, Bergen Eriksen T, et al. Omics and imaging combinatorial approach reveals butyrate-induced inflammatory effects in the zebrafish gut. Anim Microbiome. 2023;5:15. https://doi.org/10.1186/s42523-023-00230-2

33. Yadav V, Chatterjee SS, Majeed M, Kumar V. Long-lasting preventive effects of piperlongumine and a Piper longum extract against stress-triggered pathologies in mice. J Intercult Ethnopharmacol. 2015;4(4):277-83. https://doi.org/10.5455/jice.20150921010411

34. Azeez TB, Lunghar J. 5 - Antiinflammatory effects of turmeric (Curcuma longa) and ginger (Zingiber officinale). In: Gopi S, Amalraj A, Kunnumakkara A, Thomas S, editors. Inflammation and natural products. London, UK: Academic Press; 2021. pp. 83-102. https://doi.org/10.1016/B978-0-12-819218-4.00011-0

35. Selvaraj LK, Jeyabalan S, Wong LS, Sekar M, Logeshwari B, Umamaheswari S. Baicalein prevents stress-induced anxiety behaviors in zebrafish model. Front Pharmaco. 2022;13:990799. https://doi.org/10.3389/fphar.2022.990799