Evaluation of anti-nociceptive and anti-inflammatory activities of Piper sylvaticum (Roxb.) stem by experimental and computational approaches

Abstract

Piper sylvaticum Roxb., (Family: Piperaceae), commonly known as pahaari peepal, is used in traditional medicine for the treatment of rheumatic pain, headache, asthma, chronic cough, diarrhea, and wounds. To provide scientific proof for its traditional use, the present study was designed to investigate the antinociceptive and anti-inflammatory properties of methanol extract of P. sylvaticum stem (MEPSS) in pain models. Additionally, computational studies viz. molecular docking, ADME and toxicological property predictions were performed to identify the potent phytochemicals of this plant for antinociceptive and anti-inflammatory activities with good oral bioavailability and safety features. Quantitative phytochemical analysis of MEPSS was performed using established protocols. The antinociceptive activity was determined using acetic acid and formalin test in mice at the doses of 200 and 400 mg/kg while paw edema induced by carrageenan used for anti-inflammatory activity. Molecular docking study was performed by Schrödinger Maestro 10.1 whereas the SwissADME and admetSAR were used for ADME and toxicity prediction respectively. The total phenolic and flavonoid contents of MEPSS were 93.39 and 53.74 mg gallic acid and quercetin equivalent/g of extract respectively. The methanol extract exhibited significant and dose-dependent antinociceptive and anti-inflammatory effects in experimental pain models. Also, our docking study showed that piperine, piperlonguminine, and sylvamide have the best binding affinities to cyclooxygenase enzymes with good ADME/T properties. This study confirmed that MEPSS possess significant antinociceptive and anti-inflammatory activities which could be due to the presence of phytochemicals and three bioactive compounds (piperine, piperlonguminine, and sylvamide) were found to be most effective in computational studies.

This is a preview of subscription content, access via your institution.

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

Abbreviations

MEPSS:

Methanol extract of Piper sylvaticum stem

ADME:

Absorption, distribution, metabolism, elimination

p.o:

Per oral

OECD:

Organization for Economic Co-operation and Development

PDB:

Protein data bank

OPLS:

Optimized potentials for liquid simulations

RMSD:

Root-mean-square deviation

SPSS:

Statistical package for the social sciences

SEM:

Standard error of the mean

ANOVA:

Analysis of variance

References

  1. Adnan M, Chy MNU, Kamal ATMM et al (2019a) Investigation of the biological activities and characterization of bioactive constituents of ophiorrhiza rugosa var. prostrata (D. Don) and mondal leaves through In vivo, In vitro, and In silico approaches. Molecules 24:1367. https://doi.org/10.3390/molecules24071367

    CAS  Article  PubMed Central  Google Scholar 

  2. Adnan M, Chy MNU, Mostafa Kamal ATM et al (2019b) Evaluation of anti-nociceptive and anti-inflammatory activities of the methanol extract of Holigarna caustica (Dennst.) Oken leaves. J Ethnopharmacol 236:401–411. https://doi.org/10.1016/j.jep.2019.01.025

    CAS  Article  PubMed  Google Scholar 

  3. Aiyegoro OA, Okoh AI (2010) Preliminary phytochemical screening and In vitro antioxidant activities of the aqueous extract of Helichrysum longifolium DC. BMC Complement Altern Med 10:1–8

    Article  Google Scholar 

  4. Bang JS, Choi HM, Sur B-J et al (2009) Anti-inflammatory and antiarthritic effects of piperine in human interleukin 1β-stimulated fibroblast-like synoviocytes and in rat arthritis models. Arthritis Res Ther 11:R49

    Article  Google Scholar 

  5. Barik BR (1992) Premnazole an isoxazole alkaloid of Premna integrifolia and Gmelina arborea with antiinflammatory activity. Fitoterapia 63:295–299

    CAS  Google Scholar 

  6. Berman HM, Battistuz T, Bhat TN et al (2002) The protein data bank. Acta Crystallogr Sect D Biol Crystallogr 58:899–907

    Article  Google Scholar 

  7. Bley KR, Hunter JC, Eglen RM, Smith JAM (1998) The role of IP prostanoid receptors in inflammatory pain. Trends Pharmacol Sci 19:141–147

    CAS  Article  Google Scholar 

  8. Bukhari IA, Alhumayyd MS, Mahesar AL, Gilani AH (2013) The analgesic and anticonvulsant effects of piperine in mice. J Physiol Pharmacol 64:789

    CAS  PubMed  Google Scholar 

  9. Chao J, Lu T-C, Liao J-W et al (2009) Analgesic and anti-inflammatory activities of ethanol root extract of Mahonia oiwakensis in mice. J Ethnopharmacol 125:297–303

    CAS  Article  Google Scholar 

  10. Choi J, Jung H-J, Lee K-T, Park H-J (2005) Antinociceptive and anti-inflammatory effects of the saponin and sapogenins obtained from the stem of Akebia quinata. J Med Food 8:78–85

    CAS  Article  Google Scholar 

  11. Cortes-Altamirano JL, Reyes-Long S, Olmos-Hernández A et al (2018) Antinociceptive and pronociceptive effect of levetiracetam in tonic pain model. Pharmacol Rep 70:385–389

    CAS  Article  Google Scholar 

  12. De Prá SDT, Ferro PR, Milioli AM et al (2017) Antinociceptive activity and mechanism of action of hydroalcoholic extract and dichloromethane fraction of Amphilophium crucigerum seeds in mice. J Ethnopharmacol 195:283–297

    Article  Google Scholar 

  13. França DS, Souza ALS, Almeida KR et al (2001) B vitamins induce an antinociceptive effect in the acetic acid and formaldehyde models of nociception in mice. Eur J Pharmacol 421:157–164

    Article  Google Scholar 

  14. Goldberg DS, Mcgee SJ (2011) Pain as a global public health priority. BMC Public Health 11(1):770

    Article  Google Scholar 

  15. Harborne AJ (1998) Phytochemical methods a guide to modern techniques of plant analysis, 3rd edn. Springer, Dordrecht

    Google Scholar 

  16. Harman CA, Turman MV, Kozak KR et al (2007) Structural basis of enantioselective inhibition of cyclooxygenase-1 by S-alpha-substituted indomethacin ethanolamides. J Biol Chem 282:28096–28105. https://doi.org/10.1074/jbc.M701335200

    CAS  Article  PubMed  Google Scholar 

  17. Hasanat A, Chowdhury AT, Kabir SM et al (2017) Antinociceptive activity of Macaranga denticulata Muell. Arg. (Family: Euphorbiaceae): In vivo and In silico studies. Medicines. https://doi.org/10.3390/medicines4040088

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hunskaar S, Hole K (1987) The formalin test in mice: dissociation between inflammatory and non-inflammatory pain. Pain 30:103–114

    CAS  Article  Google Scholar 

  19. Ide S, Satoyoshi H, Minami M, Satoh M (2015) Amelioration of the reduced antinociceptive effect of morphine in the unpredictable chronic mild stress model mice by noradrenalin but not serotonin reuptake inhibitors. Mol Pain 11:47

    Article  Google Scholar 

  20. Ikeda Y, Ueno A, Naraba H, Oh-ishi S (2001) Involvement of vanilloid receptor VR1 and prostanoids in the acid-induced writhing responses of mice. Life Sci 69:2911–2919

    CAS  Article  Google Scholar 

  21. Kaur R, Matta T, Kaur H (2019) Plant derived alkaloids. Saudi J Life Sci 2:158–189

    Google Scholar 

  22. Koster R, Anderson M, De Beer EJ (1959) Acetic acid for analgesic screening. Proc Soc Exp Biol Med 18:412–415

    Google Scholar 

  23. Kumar K, Kumar D, Jindal DK et al (2016) Comparative antioxidant activity of roots and fruits of Piper sylvaticum (Roxb). J Compr Phar 3(4):132–135

    Article  Google Scholar 

  24. Lanhers M-C, Fleurentin J, Dorfman P et al (1991) Analgesic, antipyretic and anti-inflammatory properties of Euphorbia hirta. Planta Med 57:225–231

    CAS  Article  Google Scholar 

  25. Le Bars D, Gozariu M, Cadden SW (2001) Animal models of nociception. Pharmacol Rev 53:597–652

    PubMed  Google Scholar 

  26. Liang Y-C, Huang Y-T, Tsai S-H et al (1999) Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Carcinogenesis 20:1945–1952

    CAS  Article  Google Scholar 

  27. No OT (2001) 420: acute oral toxicity-fixed dose procedure. OECD Guidel Test Chem Sect 4:1–14

    Google Scholar 

  28. Parmar VS, Jain SC, Bisht KS et al (1997) Phytochemistry of the genus Piper. Phytochemistry 46:597–673

    CAS  Article  Google Scholar 

  29. Paul A, Adnan M, Majumder M et al (2018) Anthelmintic activity of Piper sylvaticum Roxb. (Family: Piperaceae): In vitro and in silico studies. Clin Phytosci 4:17

    Article  Google Scholar 

  30. Quattrocchi U (2012) CRC World dictionary of medicinal and poisonous plants: common names, scientific names, eponyms, synonyms, and etymology, 1st edn. CRC Press, Boca Raton

    Google Scholar 

  31. Ramprasath VR, Shanthi P, Sachdanandam P (2006) Immunomodulatory and anti-inflammatory effects of Semecarpus anacardium Linn. Nut milk extract in experimental inflammatory conditions. Biol Pharm Bull 29:693–700

    CAS  Article  Google Scholar 

  32. Roca-Vinardell A, Berrocoso E, Llorca-Torralba M et al (2018) Involvement of 5-HT1A/1B receptors in the antinociceptive effect of paracetamol in the rat formalin test. Neurobiol Pain 3:15–21

    CAS  Article  Google Scholar 

  33. Sai ePublications (2013) Knowledge of herbs, 1st edn. Andhra Pradesh

  34. Shahinozzaman M, Taira N, Ishii T et al (2018) Anti-inflammatory, anti-diabetic, and Anti-Alzheimer’s effects of prenylated flavonoids from okinawa propolis: an investigation by experimental and computational studies. Molecules 23:2479

    Article  Google Scholar 

  35. Silva DR, Baroni S, Svidzinski AE et al (2008) Anti-inflammatory activity of the extract, fractions and amides from the leaves of Piper ovatum Vahl (Piperaceae). J Ethnopharmacol 116:569–573

    Article  Google Scholar 

  36. Singh M, Kumar V, Singh I et al (2010) Anti-inflammatory activity of aqueous extract of Mirabilis jalapa Linn. leaves. Pharmacognosy Res 2:364

    Article  Google Scholar 

  37. Tasleem F, Azhar I, Ali SN et al (2014) Analgesic and anti-inflammatory activities of Piper nigrum L. Asian Pac J Trop Med 7:S461–S468

    Article  Google Scholar 

  38. Tjølsen A, Berge O-G, Hunskaar S et al (1992) The formalin test: an evaluation of the method. Pain 51:5–17

    Article  Google Scholar 

  39. Vecchio AJ, Simmons DM, Malkowski MG (2010) Structural basis of fatty acid substrate binding to cyclooxygenase-2. J Biol Chem 285:22152–22163. https://doi.org/10.1074/jbc.M110.119867

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Vezza T, Rodríguez-Nogales A, Algieri F et al (2016) Flavonoids in inflammatory bowel disease: a review. Nutrients 8:211

    Article  Google Scholar 

  41. Vinegar R, Schreiber W, Hugo R (1969) Biphasic development of carrageenin edema in rats. J Pharmacol Exp Ther 166:96–103

    CAS  PubMed  Google Scholar 

  42. Wheeler-Aceto H, Cowan A (1991) Neurogenic and tissue-mediated components of formalin-induced edema: evidence for supraspinal regulation. Agents Actions 34:264–269

    CAS  Article  Google Scholar 

  43. Xu J, Zhao Q, Wei L et al (2015) Phytochemical composition and antinociceptive activity of Bauhinia glauca subsp. hupehana in rats. PLoS ONE 10:1–13. https://doi.org/10.1371/journal.pone.0117801

    CAS  Article  Google Scholar 

  44. Yin Z-Y, Li L, Chu S-S et al (2016) Antinociceptive effects of dehydrocorydaline in mouse models of inflammatory pain involve the opioid receptor and inflammatory cytokines. Sci Rep 6:27129. https://doi.org/10.1038/srep27129

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Zakaria ZA, Sani M, Hijaz M et al (2016) Antinociceptive effect of semi-purified petroleum ether partition of Muntingia calabura leaves. Rev Bras Farmacogn 26:408–419

    CAS  Article  Google Scholar 

Download references

Acknowledgements

The authors are grateful to the Department of Pharmacy, International Islamic University Chittagong, Bangladesh for providing all the laboratory facilities and support to complete this research work. The authors are also thankful to GUSTO A Research Group for their kind help.

Author information

Affiliations

Authors

Contributions

Md. Nazim Uddin Chy, Md. Adnan and Arkajyoti Paul conceived and designed the experiments. Akash Kumar Rauniyar and Md. Moksadul Amin helped to write the original draft and contributed to data analysis. Md. Nazim Uddin Chy, Md. Adnan, Kaniz Farhana, Fayejun Nesa, Muazzem Ahmad Sany, Mohammad Akramul Hoque Tanim, and Tanvir Iqram Siddique carried out experimental works, analyzed and interpreted experimental results and wrote the manuscript. Md. Nazim Uddin Chy, Arkajyoti Paul, and Mohuya Majumder performed the computational study and wrote the relevant potion. This study was carried out in collaboration between all authors. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Md. Nazim Uddin Chy or Arkajyoti Paul.

Ethics declarations

Ethical statements

This study was carried out in accordance with the internationally accepted principle for proper use of laboratory animals namely National Institutes of Health and the International Council for Laboratory Animal Science. The present study protocol was reviewed and approved by the “P&D committee” of the Department of Pharmacy, International Islamic University Chittagong, Bangladesh with a reference number: Pharm-P&D-61/08’16-125.

Conflicts of interest

Md. Nazim Uddin Chy has no conflict of interest. Md. Adnan has no conflict of interest. Akash Kumar Rauniyar has no conflict of interest. Md. Moksadul Amin has no conflict of interest. Mohuya Majumder has no conflict of interest. Md. Sahidul Islam has no conflict of interest. Shanta Afrin has no conflict of interest. Kaniz Farhana has no conflict of interest. Fayejun Nesa has no conflict of interest. Muazzem Ahmad Sany has no conflict of interest. Mohammad Akramul Hoque Tanim has no conflict of interest. Tanvir Iqram Siddique has no conflict of interest. Arkajyoti Paul has no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chy, M.N.U., Adnan, M., Rauniyar, A.K. et al. Evaluation of anti-nociceptive and anti-inflammatory activities of Piper sylvaticum (Roxb.) stem by experimental and computational approaches. ADV TRADIT MED (ADTM) 20, 327–341 (2020). https://doi.org/10.1007/s13596-019-00395-9

Download citation

Keywords

  • Piper sylvaticum
  • Antinociceptive
  • Anti-inflammatory
  • Molecular docking
  • ADME and toxicity prediction