Skip to main content

Advertisement

SpringerLink
Log in

Fatty ethanolamide of Bertholletia excelsa triglycerides (Brazil nuts): anti-inflammatory action and acute toxicity evaluation in Zebrafish (Danio rerio)

  • Original Article
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

Fatty amides (N-alkylamides) are bioactive lipids that are widely distributed in microorganisms, animals, and plants. The low yield in the extraction process of spilantol, a fatty amide, which is mainly related to its diverse biological effects, compromises its application on a large scale. Thus, this study proposes an alternative method to synthesise fatty amides from Bertholletia excelsa (AGBe) oil, with a chemical structure similar to that of spilantol. Carrageenan-induced abdominal oedema in vivo models were used in zebrafish (Danio rerio). In in vivo studies, oral AGBe produced no signs of toxicity. In the histopathological study, AGBe did not cause significant changes in the main metabolising organs (liver, kidneys, and intestines). All doses of AGBe (100 mg/kg, 500 mg/kg, and 750 mg/kg) were effective in reducing oedema by 65%, 69%, and 95%, respectively, producing a dose–response effect compared to the control group, and spilantol-inhibited oedema by 48%. In the in silico study, with the use of molecular docking, it was observed that among the AGBe, the molecules 18:1, ω-7-ethanolamine, and 18:1, ω-9-ethanolamine stood out, with 21 interactions for COX-2 and 20 interactions for PLA2, respectively, surpassing the spilantol standard with 15 interactions for COX-2 and PLA2. The anti-inflammatory action hypothesis was confirmed in the in silico study, demonstrating the involvement of AGBe in the process of inhibiting the enzymes COX-2 and PLA2. Therefore, based on all the results obtained and the fact that until the dose of 1000 mg/kg was administered orally in zebrafish, it was not possible to determine the LD50; it can be said that AGBe is effective and safe for anti-inflammatory activity.

Graphic abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15

Similar content being viewed by others

References

  • Araújo PHF, Barata PHdS, Araújo IF, Curti JM, Amaral RR, Bereau D, Carvalho JCT, Ferreira IM (2018) Direct and solvent-free aminolysis of triglyceride from Oenocarpus bataua (Patawa) oil catalysed by Al2O3. Catal Lett 148:843–851

    Article  Google Scholar 

  • Barata P, Sarquis Í, Carvalho H, Barros A, Rodrigues A, Galue-Parra A, Silva E, Carvalho JC, Ferreira I (2020) Chemoenzymatic synthesis and anti-inflammatory activity of fatty acid amides prepared from Bertholletia excelsa (Brazil Nut) triglycerides. J Braz Chem Soc 1:1–9

    Google Scholar 

  • Barbosa AF (2015) Spilantol: occurrence, extraction, chemistry and biological activities. Rev Bras 25:128–133

    Google Scholar 

  • Borges RS, Lima ES, Keita H, Ferreira IM, Fernandes CP, Cruz RAS, Duarte JL, Velázquez-Moyado J, Ortiz BLS, Castro AN, Ferreira JV, Hage-Melim LIS, Carvalho JCT (2017) Anti-inflammatory and antialgic actions of a nanoemulsion of Rosmarinus officinalis L. essential oil and a molecular docking study of its major chemical constituents. Inflammopharmacology 26:183–195

    Article  Google Scholar 

  • Borges RS, Ortiz BL, Pereira AC, Keita H, Carvalho JC (2017) Rosmarinus officinalis essential oil: a review of its phytochemistry, antiinflammatory activity, and mechanisms of action involved. J Ethnopharmacol 229:29–45

    Article  Google Scholar 

  • Borges RS, Keita H, Ortiz BLS et al (2018) Anti-inflammatory activity of nanoemulsions of essential oil from Rosmarinus officinalis L.: in vitro and in zebrafish studies. Inflammopharmacology 26:1057–1080

    Article  CAS  Google Scholar 

  • Brugman S (2016) The zebrafish as a model to study intestinal inflammation. Dev Comp Immunol 64:82–92. https://doi.org/10.1016/j.dci.2016.02.020

    Article  CAS  PubMed  Google Scholar 

  • Carnovali M, Ottria R, Pasqualetti S, Banfi G, Ciuffreda P, Mariotti M (2016) Effects of bioactive fatty acid amide derivatives in zebrafish scale model of bone metabolism and disease. Pharmacol Res 104:1–8. https://doi.org/10.1016/j.phrs.2015.12.009

    Article  CAS  PubMed  Google Scholar 

  • Carvalho JCT, Keita H, Santana GR, Souza GC, Santos IVF, Amado JR, Kourouma A, Prada AL, Carvalho HO, Silva ML (2017) Efeitos do veneno de Bothrops alternatus no peixe-zebra: estudo histopatológico. Inflammopharmacology 25:1–9

    Article  Google Scholar 

  • Chakraborty A, Devi B, Sanjebam R, Khumbong S, Thokchom EI (2010) “Estudos preliminares sobre as atividades anestésicas e antipiréticas locais de Spilanthes Acmella Murr em modelos animais experimentais. Indian J Pharmacol 42:277–279

    Article  CAS  Google Scholar 

  • Chandak N, Kumar P, Kaushik P, Varshney P, Sharma C, Kaushik D, Jain S, Aneja KR, Sharma PK (2014) Dual evaluation of some novel 2-amino-substituted coumarinylthiazoles as anti-inflammatory-antimicrobial agents and their docking studies with COX-1/COX-2 active sites. J Enzyme Inhib Med Chem 29:476–484

    Article  CAS  Google Scholar 

  • Chunhieng T, Hafidi A, Pioch D, Brochier J, Didier M (2008) Detailed study of Brazil nut (Bertholletia excelsa) oil micro-compounds: phospholipids, tocopherols and sterols. J Braz Chem Soc 19:1374–1380

    Article  CAS  Google Scholar 

  • Cole SH, Carney GE, McClung CA, Willard SS, Taylor BJ, Hirsh J (2005) Two functional but noncomplementing. Drosophila tyrosine decarboxylase genes. J Biol Chem 280:14948–14955

    Article  CAS  Google Scholar 

  • Collymore C, Rasmussen S, Tolwani RJ (2013) Gavaging adult zebrafish. JoVE. https://doi.org/10.3791/50691

    Article  PubMed  PubMed Central  Google Scholar 

  • Da Hsu S, Chu CH, Tsou AP, Chen SJ, Chen HC, Hsu PWC, Wong YH, Chen YH, Chen GH, DA Huang H (2007) miRNAMap 2.0: genomic maps of microRNAs in metazoan genomes. Nucleic Acids 36:165–169 (Published online)

    Article  Google Scholar 

  • de Souza GC, Viana MD, Goes LDM, Sanchez-Ortiz BL, Da Silva GA, De Souza Pinheiro WB, Rodrigues dos Santos CB, Tavares Carvalho JC (2020) Reproductive toxicity of the hydroethanolic extract of the flowers of Acmella oleracea and spilanthol in zebrafish: in vivo and in silico evaluation. Hum Exp Toxicol 39(2):127–146. https://doi.org/10.1177/0960327119878257

    Article  CAS  PubMed  Google Scholar 

  • Dias AMA (2011) Spilantol from Spilanthes Acmella flowers, leaves and stems obtained by selective supercritical carbon dioxide extraction. J Supercrit Fluids 61:1–9

    Google Scholar 

  • Dos Santos SM (2015) Obtenção de spilantol a partir das folhas de jambu (Spilanthes Acmella (l) murr. Universidade Federal do Ceará, Grau de bacharel

    Google Scholar 

  • Du X, Li Y, Xia YL, Ai SM, Liang J, Sang P, Ji XL, Liu SQ (2016) Insights into protein–ligand interactions: mechanisms, models, and methods. Int J Mol Sci 17:144

    Article  Google Scholar 

  • Fiorucci S, Meli R, Bucci M, Cirino G (2001) Dual inhibitors of cyclooxygenase and 5-lipoxygenase. A new avenue in anti-inflammatory therapy? Biochem Pharmacol 62:1433–1438

    Article  CAS  Google Scholar 

  • Giordanetto F, Pettersen D, Starke I, Nordberg P, Dahlström M, Knerr L, Selmi N, Rosengren B, Larsson LO, Sandmark J, Castaldo M, Dekker N, Karlsson U, Hurt-Camejo E (2016) Discovery of AZD2716: a novel secreted phospholipase A2 (sPLA2) inhibitor for the treatment of coronary artery disease. ACS Med Chem Lett 7:884–889

    Article  CAS  Google Scholar 

  • Hage-Melim LIS, Poiani JGC, Da Silva CHTP (2019) Boylan, F. In silico study of the mechanism of action, pharmacokinetic and toxicological properties of some N-methylanthranilates and their analogs. Food Chem Toxicol 131:110556

    Article  Google Scholar 

  • Hernández I, Márquez L, Martínez I, Dieguez R, Delporte C, Prieto S, Molina-Torres J, Garrido G (2009) Anti-inflammatory effects of ethanolic extract and alkamides-derived from Heliopsis longipes roots. J Ethnopharmacol 124:649–652

    Article  Google Scholar 

  • Huang SY, Feng CW, Hung HC, Chakraborty C, Chen CH, Chen WF et al (2014) A novel zebrafish model to provide mechanistic insights into the inflammatory events in carrageenan-induced abdominal edema. PLoS ONE 9:e104414. https://doi.org/10.1371/journal.pone.0104414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kettleborough RN, Busch-Nentwich EM et al (2013) A systematic genome-wide analysis of zebrafish protein-coding gene function. Nature 496:494–497

    Article  CAS  Google Scholar 

  • Leary S, Anthony R, Cartner S, Corey D, Grandin T, Greenacre C, Gwaltney-Brant S, Mccrackin MA, Meyer R, Miller D, Shearer J, Yanong R (2013) Avma orientações para a eutanásia dos animais.

  • Li Y. -C, Chiang C -W Yeh (2008) Structures of Prostacyclin Synthase and Its Complexes with Substrate Analog and Inhibitor Reveal a Ligand-specific Heme Conformation Change H.−C, Hsu. Journal of Biological Chemistry 283(5), P-Y, Whitby, F. G, L-H, Wang, Chan, N.-L: 2917–2926

  • MacRae CA, Peterson RT (2015) Zebrafish as tools for drug discovery. Nat Rev Drug Discov 14:721–731

    Article  CAS  Google Scholar 

  • Mathur P, Lau B, Guo S (2011) Conditioned place preference behavior in zebrafish. Nat Protoc 6:338–345

    Article  CAS  Google Scholar 

  • Molina-Torres J, Salgado-Garciglia R, Ramirez-Chanez E, del Rio RE (1996) Purelyolefinic alkamides in Heliopsis longipes and Acmella (Spilanthes) oppositifolia. Biochem Syst Ecol 24:27–43

    Google Scholar 

  • Motta EV, Pinto NC, Duque AP, Mendes RF, Bellozi PM, Scio E (2013) Atividades antioxidante, antinociceptiva e anti-inflamatória das folhas de Mucuna pruriens (L.) DC. Rev Bras Plantas Med 15:264–272

    Article  CAS  Google Scholar 

  • Orlando BJ, Malkowski MG (2016) Substrate-selective inhibition of cyclooxygenase-2 by fenamic acid derivatives is dependent on peroxide tone. J Biol Chem 291:15069–15081

    Article  CAS  Google Scholar 

  • Pena Muniz MA, Ferreira Dos Santos MN, da Costa CE, Morais L, Lamarão ML, Ribeiro-Costa RM, Silva-Júnior JO (2015) Physicochemical characterization, fatty acid composition, and thermal analysis of Bertholletia excelsa HBK oil. Pharmacogn Mag 11(41):147–151. https://doi.org/10.4103/0973-1296.149730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Porres Aracama JM, Alberdi Odriozola F, García Urra F, Marco Garde P, Rekondo Andueza YM (2000) Ablación de la unión auriculoventricular en la fibrilación auricular refractaria a tratamiento farmacológico. Med Intensiva 24:8–13

    Article  Google Scholar 

  • Ribeiro LC (2013) Investigação do efeito ictiotóxico do extrato etanolico da raiz de Spilanthes Acmella (jambu) em zebrafish através da análise eletrofisiológica e comportamental. Dissertação (Mestrado em Neurociências e Biologia) Instituto de Ciências Biológicas, Universidade Federal do Pará, Belém

  • Sampaio TIS, Melo NC, Freitas Paiva BT, Silva Aleluia GA, Silva Neto FLP, Silva HR, Keita H, Cruz RAS, Sánchez-Ortiz BL, Pineda-Peña EA et al (2018) Leaves of Spondias mombin L. a traditional anxiolytic and antidepressant: Pharmacological evaluation on zebrafish (Danio rerio). J Ethnopharmacol 224:563–578. https://doi.org/10.1016/j.jep.2018.05.037

    Article  CAS  Google Scholar 

  • Sandy M, Butler A (2009) Microbial iron acquisition: marine and terrestrial siderophores. Chem Rev 109:4580–4595

    Article  CAS  Google Scholar 

  • Schmidt R, Strähle U, Scholpp S (2013) Scholpp, S. Neurogenesis in zebrafish—from embryo to adult. Neural Dev 8:3

    Article  Google Scholar 

  • Shawahna R, Jaradat NA (2017) Ethnopharmacological survey of medicinal plants used by patients with psoriasis in the West Bank of Palestine. BMC Complement Altern Med 17:4. https://doi.org/10.1186/s12906-016-1503-4

    Article  PubMed  PubMed Central  Google Scholar 

  • Silva D, De Oliveira M (2013) Atividade farmacológica e toxicológica das Flores de Acmella oleracea (L.) R. K. Jansen. Dissertação (Mestrado em recursos naturais da Amazônia)—Universidade Federal do Oeste do Pará

  • Spence R, Gerlach G, Lawrence C, Smith C (2008) The behaviour and ecology of the zebrafish, Danio rerio. Biol Rev Camb Philos Soc 83(1):13–34. https://doi.org/10.1111/j.1469-185X.2007.00030.x

    Article  PubMed  Google Scholar 

  • Souza GC, Duarte JL, Fernandes CP, Moyado JAV, Navarrete A, Carvalho JCT (2016) Obtainment and study of the toxicity of perillyl alcohol nanoemulsion on zebrafish (Danio rerio). J Nanomed Res 4:93

    Google Scholar 

  • Vitale P, Panella A, Scilimati A, Perrone MG (2016) COX-1 inhibitors: beyond structure toward therapy. Med Res Rev 36: 641–671

  • Wu LC, Fan NC, Lin MH, Chu IR, Huang SJ, Hu CY, Han SY (2008) Anti-inflammatory effect of spilantol from Spilanthes Acmella on murine macrophage by down-regulating LPS-induced inflammatory mediators. J Agric Food Chem 56:2341–2349

    Article  CAS  Google Scholar 

  • Zaa C, Valdivia M, Marcelo Á (2012) Efecto antiinflamatorio Y antioxidante del extracto Hidroalcohólico de Petiveria Alliacea. Revista peruana de biología 19: 329–334. https://doi.org/10.15381/rpb.v19i3.1049

Download references

Acknowledgements

The authors would like to thank the PAEC OEA/GCUB Program No. 001/2018, under the cooperation agreement between the Organization of American States (OAS) and the Coimbra Group of Brazilian Universities (CGUB) for the financial support for student YFQU.

Author information

Authors and Affiliations

  1. Programa de Pós-Graduação em Ciências Farmacêuticas, Departamento de Ciências Biológicas e da Saúde, Curso de Farmácia, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil

    Yesica Fernanda Quitian-Useche, Swanny Ferreira Borges, Lorane Izabel da Silva Hage Melim, Irlon Maciel Ferreira, José Carlos Tavares Carvalho & Raphaelle Sousa Borges

  2. Laboratório de Pesquisa em Fármacos, Departamento de Ciências Biológicas e da Saúde, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil

    Yesica Fernanda Quitian-Useche, Brenda Lorena Sánchez-Ortiz, Swanny Ferreira Borges, Gisele Custódio de Souza, José Carlos Tavares Carvalho & Raphaelle Sousa Borges

  3. Laboratório de Biocatálise e Síntese Orgânica Aplicada, Departamento de Ciências Exatas, Curso de Química, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil

    Benilson Ramos & Irlon Maciel Ferreira

  4. Laboratório de Química Farmacêutica e Medicinal (PharMedChem), Departamento de Ciências Biológicas e da Saúde, Curso de Farmácia, Universidade Federal do Amapá, Rod. JK, km 02, Macapá, Amapá, 68902-280, Brazil

    Mateus Alves Batista & Lorane Izabel da Silva Hage Melim

Authors
  1. Yesica Fernanda Quitian-Useche
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Brenda Lorena Sánchez-Ortiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Swanny Ferreira Borges
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Benilson Ramos
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gisele Custódio de Souza
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mateus Alves Batista
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lorane Izabel da Silva Hage Melim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Irlon Maciel Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. José Carlos Tavares Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Raphaelle Sousa Borges
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BR obtained and characterised AGBe under the guidance of the IMF. In vivo biological assays were performed using YFQU and SFB with GCS, BLSO, and RSB. LISHM carried out the in silico study, and JCTC participated as the general coordinator of the study and reviewer of the data obtained.

Corresponding author

Correspondence to Raphaelle Sousa Borges.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Quitian-Useche, Y.F., Sánchez-Ortiz, B.L., Borges, S.F. et al. Fatty ethanolamide of Bertholletia excelsa triglycerides (Brazil nuts): anti-inflammatory action and acute toxicity evaluation in Zebrafish (Danio rerio). Inflammopharmacol 29, 1519–1537 (2021). https://doi.org/10.1007/s10787-021-00867-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-021-00867-y

Keywords

Search

Navigation