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Stephalagine, an aporphine alkaloid from Annona crassiflora fruit peel, induces antinociceptive effects by TRPA1 and TRPV1 channels modulation in mice.
Bioorg Chem. 2020 03; 96:103562.BC

Abstract

Pain relief represents a critical unresolved medical need. Consequently, the search for new analgesic agents is intensively studied. Annona crassiflora, a native species of the Brazilian Savanna, represents a potential source for painful treatment. This study aimed to investigate the antinociceptive potential of A. crassiflora fruit peel, focusing on its major alkaloid, stephalagine, in animal models of pain evoked by the activation of transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) channels. Male C57BL/6/J mice were submitted to formalin-, cinnamaldehyde-, and capsaicin-induced nociception tests to assess nociceptive behavior, and to the open-field and rotarod tests for motor performance analyses. Moreover, the stephalagine's effect was tested on capsaicin- and cinnamaldehyde-induced Ca2+ influx in spinal cord synaptosomes. In silico assessments of the absorption, distribution, metabolism and central nervous system permeability of stephalagine were carried out. The ethanol extract and alkaloidal fraction reduced the nociception induced by formalin. When administered by oral route (1 mg/kg), stephalagine reduced the spontaneous nociception and paw edema induced by TRPV1 agonist, capsaicin, and by TRPA1 agonists, cinnamaldehyde- and formalin, without altering the animals' locomotor activity. The prediction of in silico pharmacokinetic properties of stephalagine suggests its capacity to cross the blood-brain barrier. Furthermore, this alkaloid reduces the capsaicin- and cinnamaldehyde-mediated Ca2+ influx, indicating a possible modulation of TRPV1 and TRPA1 channels, respectively. Together, our results support the antinociceptive and anti-edematogenic effects of the A. crassiflora fruit peel and suggest that these effects are triggered, at least in part, by TRPV1 and TRPA1 modulation by stephalagine.

Authors+Show Affiliations

Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, 38408-100 Uberlândia, MG, Brazil.Graduate Program in Chemistry, Institute of Chemistry, Federal University of Uberlândia, 38400-902 Uberlândia, MG, Brazil.Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, 38408-100 Uberlândia, MG, Brazil.Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, 38408-100 Uberlândia, MG, Brazil.Graduate Program in Biological Sciences: Toxicological Biochemistry, Biochemistry and Molecular Biology Department, Federal University of Santa Maria (UFSM), 97105-900 Santa Maria, RS, Brazil.Graduate Program in Biological Sciences: Toxicological Biochemistry, Biochemistry and Molecular Biology Department, Federal University of Santa Maria (UFSM), 97105-900 Santa Maria, RS, Brazil.Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, 38408-100 Uberlândia, MG, Brazil.Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, 38408-100 Uberlândia, MG, Brazil.Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, 38408-100 Uberlândia, MG, Brazil.Graduate Program in Biological Sciences: Toxicological Biochemistry, Biochemistry and Molecular Biology Department, Federal University of Santa Maria (UFSM), 97105-900 Santa Maria, RS, Brazil.Graduate Program in Chemistry, Institute of Chemistry, Federal University of Uberlândia, 38400-902 Uberlândia, MG, Brazil.Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, 38408-100 Uberlândia, MG, Brazil.Graduate Program in Genetics and Biochemistry, Institute of Biotechnology, Federal University of Uberlândia, 38408-100 Uberlândia, MG, Brazil. Electronic address: cassia.regina@ufu.br.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31981911

Citation

Justino, Allisson Benatti, et al. "Stephalagine, an Aporphine Alkaloid From Annona Crassiflora Fruit Peel, Induces Antinociceptive Effects By TRPA1 and TRPV1 Channels Modulation in Mice." Bioorganic Chemistry, vol. 96, 2020, p. 103562.
Justino AB, Barbosa MF, Neves TV, et al. Stephalagine, an aporphine alkaloid from Annona crassiflora fruit peel, induces antinociceptive effects by TRPA1 and TRPV1 channels modulation in mice. Bioorg Chem. 2020;96:103562.
Justino, A. B., Barbosa, M. F., Neves, T. V., Silva, H. C. G., Brum, E. D. S., Fialho, M. F. P., Couto, A. C., Saraiva, A. L., Avila, V. M. R., Oliveira, S. M., Pivatto, M., Espindola, F. S., & Silva, C. R. (2020). Stephalagine, an aporphine alkaloid from Annona crassiflora fruit peel, induces antinociceptive effects by TRPA1 and TRPV1 channels modulation in mice. Bioorganic Chemistry, 96, 103562. https://doi.org/10.1016/j.bioorg.2019.103562
Justino AB, et al. Stephalagine, an Aporphine Alkaloid From Annona Crassiflora Fruit Peel, Induces Antinociceptive Effects By TRPA1 and TRPV1 Channels Modulation in Mice. Bioorg Chem. 2020;96:103562. PubMed PMID: 31981911.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Stephalagine, an aporphine alkaloid from Annona crassiflora fruit peel, induces antinociceptive effects by TRPA1 and TRPV1 channels modulation in mice. AU - Justino,Allisson Benatti, AU - Barbosa,Marilia Fontes, AU - Neves,Thiago Vieira, AU - Silva,Heitor Cappato Guerra, AU - Brum,Evelyne da Silva, AU - Fialho,Maria Fernanda Pessano, AU - Couto,Ana Cláudia, AU - Saraiva,André Lopes, AU - Avila,Veridiana de Melo Rodrigues, AU - Oliveira,Sara Marchesan, AU - Pivatto,Marcos, AU - Espindola,Foued Salmen, AU - Silva,Cassia Regina, Y1 - 2020/01/16/ PY - 2019/10/24/received PY - 2019/12/03/revised PY - 2019/12/28/accepted PY - 2020/1/26/pubmed PY - 2021/3/12/medline PY - 2020/1/26/entrez KW - Annona crassiflora Mart. KW - Capsaicin KW - Cinnamaldehyde KW - Pain SP - 103562 EP - 103562 JF - Bioorganic chemistry JO - Bioorg Chem VL - 96 N2 - Pain relief represents a critical unresolved medical need. Consequently, the search for new analgesic agents is intensively studied. Annona crassiflora, a native species of the Brazilian Savanna, represents a potential source for painful treatment. This study aimed to investigate the antinociceptive potential of A. crassiflora fruit peel, focusing on its major alkaloid, stephalagine, in animal models of pain evoked by the activation of transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) channels. Male C57BL/6/J mice were submitted to formalin-, cinnamaldehyde-, and capsaicin-induced nociception tests to assess nociceptive behavior, and to the open-field and rotarod tests for motor performance analyses. Moreover, the stephalagine's effect was tested on capsaicin- and cinnamaldehyde-induced Ca2+ influx in spinal cord synaptosomes. In silico assessments of the absorption, distribution, metabolism and central nervous system permeability of stephalagine were carried out. The ethanol extract and alkaloidal fraction reduced the nociception induced by formalin. When administered by oral route (1 mg/kg), stephalagine reduced the spontaneous nociception and paw edema induced by TRPV1 agonist, capsaicin, and by TRPA1 agonists, cinnamaldehyde- and formalin, without altering the animals' locomotor activity. The prediction of in silico pharmacokinetic properties of stephalagine suggests its capacity to cross the blood-brain barrier. Furthermore, this alkaloid reduces the capsaicin- and cinnamaldehyde-mediated Ca2+ influx, indicating a possible modulation of TRPV1 and TRPA1 channels, respectively. Together, our results support the antinociceptive and anti-edematogenic effects of the A. crassiflora fruit peel and suggest that these effects are triggered, at least in part, by TRPV1 and TRPA1 modulation by stephalagine. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/31981911/Stephalagine_an_aporphine_alkaloid_from_Annona_crassiflora_fruit_peel_induces_antinociceptive_effects_by_TRPA1_and_TRPV1_channels_modulation_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0045-2068(19)31808-5 DB - PRIME DP - Unbound Medicine ER -