pp 1–14 | Cite as

Psychotria leiocarpa Extract and Vincosamide Reduce Chemically-Induced Inflammation in Mice and Inhibit the Acetylcholinesterase Activity

  • Anelise Samara Nazari FormagioEmail author
  • Carla Roberta Ferreira Volobuff
  • Candida Aparecida Leite Kassuya
  • Claudia Andréa Lima Cardoso
  • Maria do Carmo Vieira
  • Zefa Valdevina Pereira
  • Mariane Cristovão Bagatin
  • Gisele de Freitas Gauze


Species from Psychotria are used in folk medicine against inflammatory diseases, respiratory disturbances, and anti-hallucinogenic. In the present study, the compound vincosamide (PL-1) was identified for the first time in methanolic extract of the Psychotria leiocarpa (ME-PL) leaves, as well as the anti-inflammatory and anticholinesteric effects in rodents and molecular docking simulations. The fractionation of the chloroform fraction (CF-PL) through chromatographic methods afforded the known compound PL-1. The anti-inflammatory activity of the ME-PL (30, 100, and 300 mg/kg) and PL-1 (3, 30, and 100 mg/kg) was analyzed using experimental models: paw edema, pleurisy, and mechanical and thermal hyperalgesia induced by carrageenan. The anticholinesterase activity of the ME-PL (30 and 100 mg/kg) and PL-1 (30 mg/kg) was showed by acetylcholinesterase (AChE) inhibitory in brain structures. The molecular docking simulations were performed using Molegro Virtual Docker v6.0. Overall, the results indicated that ME-PL and PL-1 demonstrated an anti-edematogenic effect in Cg-induced paw edema, leukocyte migration in the pleurisy model, and significantly reduced mechanical hyperalgesia, cold response to acetone in mice. The samples exhibited maximal inhibition of enzyme acetylcholinesterase (AChE) in the frontal cortex. The molecular coupling of PL-1 with the AChE showed significant interactions with the catalytic and peripheral site, corroborating the activity presented in the inhibition assay. The acute administration of ME-PL did not cause signs of toxicity in the treated animals. The results showed that P. leiocarpa inhibited AChE and anti-inflammatory activity, and alkaloid vincosamide could be responsible, at least in part, for the observed effects, supporting the popular use of this genus.


Grandiúva-de-anta alkaloid acetylcholinesterase inflammation carrageenan molecular docking 



The authors are grateful to FUNDECT (Fundação de Apoio ao Desenvolvimento do Ensino, Ciência e Tecnologia do Estado de Mato Grosso do Sul; 59/300.029/2015) and Capes (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior; 2764/2011) for financial support and fellowships.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.

Ethical Approval

All experimental procedures were carried out in accordance with the U.S. National Institutes of Health and were approved by the Animal Ethics Committee from UFGD (Nbr. 14/2015).


  1. 1.
    Smith, L.B., and R.J. Downs. 1956. Resumo preliminar das rubiáceas de Santa Catarina. Sellowia 7: 13–86.Google Scholar
  2. 2.
    Souza, R.K.D., A.N.A.M. Mendonça, and M.A.P. da Silva. 2013. Aspectos etnobotânicos, fitoquímicos e farmacológicos de espécies de Rubiaceae no Brasil. Revista Cubana de Plantas Medicinales 18: 140–156.Google Scholar
  3. 3.
    Grenand, P., C. Moretti, and H. Jacquemim. 1987. Pharmacopées traditionelles en Guyane, 379–382. Paris: Editions de I’ORSTON.Google Scholar
  4. 4.
    Schultes, R.E., and R.F. Rauffauf. 1990. The healing forest. Medicinal and toxic plants of the Northwest Amazonia, 392–396. Portland: Dioscorides Press Scholar
  5. 5.
    Caballero-George, C., P.M.L. Vanderheyden, P.N. Solis, L. Pieters, A.A. Shahat, M.P. Gupta, G. Vauquelin, and A.J. Vlietnick. 2001. Biological screening of selected medicinal Panamenian plants by radioligand-binding techniques. Phytomedicine 8: 59–70. Scholar
  6. 6.
    Lopes, S.O. 1998. Análise química e cultivo in vitro de Psychotria leiocarpa Cham. et Schlecht. e Psychotria carthagenensis Jacq. (Rubiaceae). Master Thesis, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.Google Scholar
  7. 7.
    Matsuura, H.N., and A.G. Fett-Neto. 2013. The major indole alkaloid N, β-D-glucopyranosyl vincosamide from leaves of Psychotria leiocarpa Cham. & Schltdl. Is not an antifeedant but shows broad antioxidant activity. Natural Product Research 27: 402–411. Scholar
  8. 8.
    Lopes, S., G.L. Von Poser, V.A. Kerber, F.M. Farias, E.L. Konrath, P. Moreno, M.E. Sobral, J.A.S. Zuanazzi, and A.T. Henriques. 2004. Taxonomic significance of alkaloids and iridoid glucosides in the tribe Psychotrieae (Rubiaceae). Biochemical Systematics and Ecology 32: 1187–1195. Scholar
  9. 9.
    Andrade, J.M.M., R. Biegelmeyer, C.A.G. Xavier, S.A.L. Bordignon, P.R.H. Moreno, J.A.S. Zuanazzi, A.T. Henriques, and M.A. Apel. 2010. Essential oil constituents of Psychotria leiocarpa. Chemistry of Natural Compounds 46: 649–650. Scholar
  10. 10.
    Moraes, T.M.S., M.H. de Araújo, N.R. Bernardes, D.B. de Oliveira, E.B. Lasunskaia, M.F. Muzitano, and M. da Cunha. 2011. Antimycobacterial activity and alkaloid prospection of Psychotria species (Rubiaceae) from the Brazilian Atlantic Rainforest. Planta Medica 77: 964–970. Scholar
  11. 11.
    Elisabetsky, E., T.A. Amador, M.B. Leal, D.S. Nunes, A.C.T. Carvalho, and L. Verotta. 1997. Merging ethnopharmacology with chemotaxonomy: an approach to unveil bioactive natural products. The case of Psychotria alkaloids as potential analgesics. Ciência e Cultura 49: 378–385.Google Scholar
  12. 12.
    McKenna, D.J., G.N.T. Towers, and F. Abbot. 1984. Monoamine oxidase inhibitors in South American hallucinogenic plants: trypatamine and β-carboline constituents of Ayahusca. Journal of Ethnopharmacology 10: 195–223. Scholar
  13. 13.
    Formagio, A.S.N., C.R.F. Volobuff, M. Santiago, C.A.L. Cardoso, M.C. Vieira, and Z.V. Pereira. 2014. Evaluation of antioxidante activity, total flavonoids, tannins and phenolic compounds in Psychotria leaf extracts. Antioxidants 3: 745–757. Scholar
  14. 14.
    Ribeiro, M.A.S., C.M.B. Gomes, A.S.N. Formagio, Z.V. Pereira, U.Z. Melo, E.A. Basso, W.F. da Costa, D.C. Baldoqui, and M.H. Sarragiotto. 2016. Structural characterization of dimeric índole alkaloids from Psychotria brachybotrya by NMR spectroscopy and theoretical calculations. Tetrahedron Letters 57: 1331–1334. Scholar
  15. 15.
    Goschorska, M., I. Baranowska-Bosiacka, I. Gutowska, M. Tarnowski, K. Piotrowska, E. Metryka, K. Safranow, and Chlubek. 2018. Effect of acetylcholinesterase inhibitors donepezil and rivastigmine on the activity and expression of cyclooxygenases in a model of the inflammatory action of fluoride on macrophages obtained from THP-1 monocytes. Toxicology 9-20: 406–407. Scholar
  16. 16.
    Henriques, M.G., P.M. Silva, M.A. Martins, C.A. Flores, F.Q. Cunha, J. Assreuy-Filho, and R.S. Cordeiro. 1987. Mouse paw edema. A new model for inflammation. Brazilian Journal of Medical and Biological Research 20: 243–249.Google Scholar
  17. 17.
    Vinegar, R., J.F. Traux, and J.L. Selph. 1973. Some quantitative temporal characteristic of carrageenin-induced pleurisy in the rat. Proceedings of the Society for Experimental Biology and Medicine 143: 711–714. Scholar
  18. 18.
    Faria, E.O., L. Kato, C.M.A. de Oliveira, B.G. Carvalho, C.C. Silva, L.S. Sales, I.T.A. Schuquel, E.P. Silveira-Lacerda, and P.G. Delprete. 2010. Quaternary β-carboline alkaloids from Psychotria prunifolia (Kunth) Steyerm. Phytochemistry Letters 3: 133–116. Scholar
  19. 19.
    Ito, S., E. Okuda-Ashitaka, and T. Minami. 2001. Central and peripheral roles of prostaglandins in pain their interactions with novel neuropeptides nociceptin and nocistatin. Neuroscience Research 41: 299–332. Scholar
  20. 20.
    Decosterd, I., and C.J. Woolf. 2000. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87: 149–158. Scholar
  21. 21.
    Ellman, G.L., K.D. Courtney, V. Anres, and R.M. Featherstone. 1961. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology 7: 88–95. Scholar
  22. 22.
    Bradford, M.M. 1976. A rapid and sensitive method for quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical 72: 248–254. Scholar
  23. 23.
    Thomsen, R., and M.K. Christensen. 2006. MolDock. A new technique for high-accuracy molecular docking. Journal of Medicinal Chemistry 49: 3315–3321. Scholar
  24. 24.
    OECD. Test No. 425: Acute oral toxicity: up-and-down procedure. Guidelines for the testing of chemicals. 2008.
  25. 25.
    ANVISA. 2013 Guia para a condução de estudos não clínicos de toxicologia e segurança farmacológica necessários ao desenvolvimento de medicamentos. 2 ed: Gerência de Avaliação de Segurança e Eficácia – GESEF; Brasília, p. 1–48.Google Scholar
  26. 26.
    Bernard, P., D.B. Kireev, J.R. Chrétien, P.L. Fortier, and L. Coppet. 1999. Automated docking of 82 N-benzylpiperidine derivatives to mouse acetylcholinesterase and comparative molecular field analysis with ‘natural’ alignment. Journal of Computer-Aided Molecular Design 13: 355–371. Scholar
  27. 27.
    Bourne, Y., Z. Radic, G. Sulzenbacher, E. Kim, P. Taylor, and P. Marchot. 2006. Substrate and product trafficking through the active center gorge of acetylcholinesterase analyzed by crystallography and equilibrium binding. The Journal of Biological Chemistry 281: 29256–29267. Scholar
  28. 28.
    Faria, E.O. 2009. Estudo fitoquímico das folhas de Psychotria prunifolia (Kunth) Steyerm (Rubiaceae)”. M. Sc. Thesis – Universidade Federal de Goiás.Google Scholar
  29. 29.
    Erdelmeier, C.A.J., A.D. Wright, J. Orjala, B. Baumgartner, T. Rali, and O. Sticher. 1991. New indole alkaloid glycosides from Nauclea orientalis. Planta Medica 57: 149–152. Scholar
  30. 30.
    Henriques, A.T., S.O. Lopes, J.T. Paranhos, T.S. Gregianini, A.G. Fett-Neto, J. Schripsema, and G.L. Von Poser. 2004. N, β-D-glucopyranosyl vincosamide, a light regulated índole alkaloid from the shoots of Psychotria leiocarpa. Phytochemistry 65: 449–454. Scholar
  31. 31.
    Farias, F.M., C.S. Passos, M.D. Arbo, J.A. Zuanazzi, V.M. Steffen, and A.T. Henriques. 2010. Monoamine levels in rat striatum after acute intraperitoneal injection of strictosidinic acid isolated from Psychotria myriantha Mull. Arg. (Rubiaceae). Phytomedicine 17: 289–291. Scholar
  32. 32.
    Both, F.L., V.A. Kerber, A.T. Henriques, and E. Elisabetsky. 2002. Analgesic properties of umbellatine from Psychotria umbellate. Pharmaceutical Biology 40: 336–341. Scholar
  33. 33.
    Both, F.L., L. Meneghini, V.A. Kerber, A.T. Henriques, and E. Elisabetsky. 2005. Psychopharmacological profile of the alkaloid psychollatine as a 5HT2A/C serotonin modulator. Journal of Natural Products 68: 374–380. Scholar
  34. 34.
    Both, F.L., L. Meneghini, V.A. Kerber, A.T. Henriques, and E. Elisabetsky. 2006. Role of glutamate and dopamine receptors in the psychopharmacological profile of the indole alkaloid psychollatine. Journal of Natural Products 69: 342–345. Scholar
  35. 35.
    Farias, F.M., C.S. Passos, M.D. Arbo, D.M. Barros, C. Gottfried, V.M. Steffen, and A.T. Henriques. 2012. Strictosidinic acid, isolated from Psychotria myriantha Mull. Arg. (Rubiaceae), decreases serotonin levels in rat hippocampus. Fitoterapia 86: 1138–1143. Scholar
  36. 36.
    Simões-Pires, C.A., F.M. Farias, A. Marston, E.F. Queiroz, C.G. Chaves, A.T. Henriques, and K. Hostettmann. 2006. Indole monoterpenes with antichemotactic activity from Psychotria myriantha: chemotaxonomic significance. Natural Products Communications 1: 1101–1106. Scholar
  37. 37.
    Calixto, N.O., M.S. Cordeiro, T.B.S. Giorno, G.G. Oliveira, N.P. Lopes, P.D. Fernandes, A.C. Pinto, and C.M. Rezende. 2017. Chemical constituents of Psychotria nemorosa Gardner and antinociceptive activity. Journal of the Brazilian Chemical Society 28: 707–723. Scholar
  38. 38.
    Amador, T.A., L. Verotta, D.S. Nunes, and E. Elisabetsky. 2001. Involvement of NMDA receptors in the analgesic properties of psychotridine. Phytochemistry 8: 202–206. Scholar
  39. 39.
    Moura, L.T.S., Maruo, V.M. 2014. Aspectos farmacológicos e toxicológicos de Psychotria colorata - Revisão. Revista Científica Eletrônica de Medicina Veterinária 23: 1–16.Google Scholar
  40. 40.
    Porto, D.D., A.T. Henriques, and A.G. Fett-Neto. 2009. Bioactive alkaloids from South American Psychotria and related species. The Open Bioactive Compounds 2: 29–36. Scholar
  41. 41.
    Nantel, F., D. Denis, R. Gordon, A. Northey, M. Cirino, K.M. Metters, and C.C. Chan. 1999. Distribution and regulation of cyclooxygenase-2 in carrageenan induced inflammation. British Journal of Pharmacology 128: 853–859. Scholar
  42. 42.
    Seibert, K., Y. Zhang, K. Leahy, S. Hauser, J. Masferrer, W. Perkins, L. Lee, and P. Isakson. 1994. Pharmacological and biochemical demonstration of the role of cyclooxygenase 2 in inflammation and pain. Proceedings of the National Academy of Sciences of the United States of America 91: 12013–12017. Scholar
  43. 43.
    Li, D.Y., J.Q. Chen, J.Q. Ye, X.T. Zhai, J. Song, C.H. Jiang, J. Wang, H. Zhang, X.B. Jia, and F.X. Zhu. 2017. Anti-inflammatory effect of the six compounds isolated from Nauclea officinalis Pierrc ex Pitard, and molecular mechanism of strictosamide via suppressing the NF-κB and MAPK signaling pathway in LPS-induced RAW 264.7 macrophages. Journal of Ethnopharmacology 196: 66–74. Scholar
  44. 44.
    da Silva, É.R.S., G.R. Salmazzo, J. da Silva Arrigo, R.J. Oliveira, C.A.L. Kassuya, and C.A.L. Cardoso. 2016. Anti-inflammatory evaluation and toxicological analysis of Campomanesia xanthocarpa Berg. Inflammation 39: 1462–1468. Scholar
  45. 45.
    Wang, H., M. Yu, M. Ochani, C.A. Amelia, M. Tanovic, S. Susarla, J.H. Li, H. Wang, H. Yang, L. Ulloa, Y. Al-Abed, C.J. Czura, and K.J. Tracey. 2003. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 421: 384–388. Scholar
  46. 46.
    Pick, M., C. Flores-Flores, D. Grisaru, S. Shochat, V. Deutsch, and H. Soreq. 2004. Blood-cell-specific acetylcholinesterase splice variations under changing stimuli. International Journal of Developmental Neuroscience 22: 523–531. Scholar
  47. 47.
    Enz, A., R. Amstutz, H. Boddeke, G. Gmelin, and J. Malanowski. 1993. Brain selective inhibition of acetylcholinesterase: a novel approach to therapy for Alzheimer’s disease. Progress in Brain Research 98: 431–445. Scholar
  48. 48.
    Passos, C.S., C.A. Simões-Pires, A. Nurisso, T.C. Soldi, L. Kato, C.M. de Oliveira, E.O. de Faria, L. Marcourt, C. Gottfried, P.A. Carrupt, and A.T. Henriques. 2013. Indole alkaloids of Psychotria as multifunctional cholinesterases and monoamine oxidases inhibitors. Phytochemistry 86: 8–20. Scholar
  49. 49.
    Peña-Bautista, C., M. Baquero, M. Vento, and C. Cháfer-Pericás. 2019. Free radicals in Alzheimer’s disease: lipid peroxidation biomarkers. Clinica Chimica Acta 491: 85–90. Scholar
  50. 50.
    Wojtunik-Kulesza, K.A., A. Oniszczuk, T. Oniszczuk, and M. Waksmundzka-Hajnos. 2016. The influence of commom free radicals and antioxidants on development of Alzheimer’s disease. Biomedicine & Pharmacotherapy 78: 39–49. Scholar
  51. 51.
    Molina, R., A. González, M. Stelter, I. Pérez-Dorado, R. Kahn, M. Morales, M. Moscoso, S. Campuzano, N.E. Campillo, S. Mobashery, P. García, and J.A. Hermoso. 2009. Crystal structure of CbpF, a bifunctional choline-binding protein and autolysis regulator from Streptococcus pneumoniae. European Molecular Biology Organization 10: 246–251. Scholar
  52. 52.
    Bagatin, M.C., A.A. Cândido, G.M.S. Pinheiro, N.F. Höehr, M. Machinski Jr., S.A.G. Mossini, E.A. Basso, and G.F. Gauze. 2013. Molecular modeling and anticholinesterasic activity of novel 2-arylaminocyclohexyl N,N-dimethylcarbamates. Journal of the Brazilian Chemical Society 24: 1798–1807. Scholar
  53. 53.
    Bourne, Y., P. Taylor, P.E. Bougis, and P. Marchot. 1999. Crystal structure of mouse acetylcholinesterase. The Journal of Biological Chemistry 74: 2963–2970. Scholar
  54. 54.
    Guo, J., M.M. Hurley, J.B. Wright, and G.H. Lushington. 2004. A docking score function for estimating ligand-protein interactions: application to acetylcholinesterase inhibition. Journal of Medicinal Chemistry 47: 5492–5500. Scholar
  55. 55.
    Ordentlich, A., D. Barak, C. Kronman, Y. Flashner, M. Leitner, Y. Segall, N. Ariel, S. Cohen, B. Velan, and A. Shafferman. 1993. Dissection of the human acetylcholinesterase active center determinants of substrate specificity. Identification of residues constituting the anionic site, the hydrophobic site, and the acyl pocket. Journal of Medicinal Chemistry 268: 17083–17095.Google Scholar
  56. 56.
    Bartus, R.T., R.L.I. Dean, B. Beer, and A.S. Lippa. 1982. The cholinergic hypothesis of geriatric memory dysfunction. Science 217: 408–417. Scholar
  57. 57.
    Coyle, J.T., D.L. Price, and M.R. DeLong. 1983. Alzheimer’s disease: a disorder of cortical cholinergic neurons. Science 219: 1184–1190. Scholar
  58. 58.
    Battisti, V., M.R.C. Schetinger, L.D.K. Maders, K.F. Santos, M.D. Bagatini, M.C. Correa, R.M. Spanevello, M.C. Araújo, and V.M. Morsh. 2009. Changes in acetylcholinesterase (AchE) activity in lymphocytes and whole blood in acute lymphoblastic leukemia patients. Clinica Chimica Acta 402: 114–118. Scholar
  59. 59.
    Schmatz, R., C.M. Mazzanti, R. Spanevello, N. Stefanello, J. Gutierres, M. Corrêa, M.M. da Rosa, M.A. Rubin, M.R.C. Schetinger, and V.M. Morsch. 2009. Resveratrol prevents memory deficits and the increase in acetylcholinesterase activity in streptozotocin-induced diabetic rats. European Journal of Pharmacology 610: 42–48. Scholar
  60. 60.
    Mazzanti, C.M., R. Spanevello, M. Ahmed, L.B. Pereira, J.F. Gonçalves, M. Corrêa, R. Schmatz, N. Stefanello, D.B.R. Leal, A. Mazzanti, A.T. Ramos, T.B. Martins, C.C. Danesi, D.L. Graça, V.M. Morsch, and M.R.C. Schetinger. 2009. Pre-treatment with ebselen and vitamin E modulate acetylcholinesterase activity: interaction with demyelinating agents. International Journal of Developmental Neuroscience 27: 73–80. Scholar
  61. 61.
    Kaizer, R.R., J.M. Gutierres, R. Schmatz, R.M. Spanevello, V.M. Morsch, M.R.C. Schetinger, and J.B.T. Rocha. 2010. In vitro and in vivo interactions of aluminum on NTPDase and AChE activities in lymphocytes of rats. Cellular Immunology 265: 133–138. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Anelise Samara Nazari Formagio
    • 1
    • 2
    Email author
  • Carla Roberta Ferreira Volobuff
    • 2
  • Candida Aparecida Leite Kassuya
    • 2
  • Claudia Andréa Lima Cardoso
    • 3
  • Maria do Carmo Vieira
    • 4
  • Zefa Valdevina Pereira
    • 1
  • Mariane Cristovão Bagatin
    • 5
  • Gisele de Freitas Gauze
    • 5
  1. 1.Faculty of Biological and Environmental SciencesFederal University of Grande Dourados UFGDDouradosBrazil
  2. 2.Faculty of Health SciencesFederal University of Grande Dourados UFGDMato GrossoBrazil
  3. 3.Course of ChemistryUniversity of Mato Grosso do Sul UEMSMato GrossoBrazil
  4. 4.Faculty of Agricultural ScienceFederal University of Grande Dourados UFGDMato GrossoBrazil
  5. 5.Department of ChemistryState University of Maringá UEMParanáBrazil

Personalised recommendations