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Planta Med 2021; 87(05): 383-394
DOI: 10.1055/a-1264-0572
Biological and Pharmacological Activity
Original Papers

Identification of TRPV1 Ion Channels Agonists of Tropaeolum tuberosum in Human Skin Keratinocytes

Luis Apaza Ticona 
1   Department of Organic Chemistry, Faculty of Sciences, University Autónoma of Madrid, Madrid, Spain
2   Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, University Complutense of Madrid, Madrid, Spain
,
Ángel Rumbero Sánchez
1   Department of Organic Chemistry, Faculty of Sciences, University Autónoma of Madrid, Madrid, Spain
,
Cristina Thiebaut Estrada
3   Department of Research and Development, COBIOSA, Madrid, Spain
,
Olga M. Palomino 
2   Department of Pharmacology, Pharmacognosy and Botany, Faculty of Pharmacy, University Complutense of Madrid, Madrid, Spain
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Abstract

Tropaeolum tuberosum, commonly known as Mashua, is an herbal remedy used in traditional Andean medicine for the relief of kidney and bladder pain, as well as contusions. This study aimed to evaluate the fractions and isolated compounds from T. tuberosum with analgesic activity mediated by the transient receptor potential vanilloid-1 receptor. A bioguided phytochemical analysis based on NMR/MS was performed to identify the compounds of the n-heptane fractions from samples of purple tubers of T. tuberosum. The transient receptor potential vanilloid-1 agonist and antagonist activity were assessed through the measurement of intracellular Ca2+ in HEK001 cells. The chemical structure determination led to the identification of two alkamides: N-(2-hydroxyethyl)-7Z,10Z,13Z,16Z-docosatetraenamide (1) and N-oleoyldopamine (2). Both compounds induced increased intracellular calcium flow with IC50 values of 3.2 nM and 7.9 nM, respectively, thus activating the transient receptor potential vanilloid-1 receptor. Our research is the first report to show that these two compounds isolated from T. tuberosum can act as agonists of the transient receptor potential vanilloid-1 receptor, providing scientific evidence for the traditional use of this species in pain relief.

Key words

Tropaeolaceae - Tropaeolum tuberosum - alkamides - vanilloid - analgesic - TRPV1

Supporting Information

    1H- and 13C- NMR, 1H-1H COSY, HSQC, HMQC, HMBC, and MS spectra for the different fractions assayed in this study, together with isolated compounds 1 and 2, are provided as Supporting Information (Figs. 1S–23S). The activity data of the T. tuberosum fractions from the different samples are also provided as Supporting Information (Tables 1S–4S).

  • Supporting Information


Publication History

Received: 10 April 2020

Accepted after revision: 07 September 2020

Article published online:
02 October 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Apaza Ticona LN, Tena Pérez V, Bermejo Benito P. Local/traditional uses, secondary metabolites and biological activities of Mashua (Tropaeolum tuberosum Ruíz & Pavón). J Ethnopharmacol 2020; 247: 112152
    CrossrefPubMedGoogle Scholar
  • 2 De Lucca DM, Zalles AJ. Utasan Utjir Qollanaka. Medicinas junto a nuestra casa, 1ra edición. La Paz: Agencia Española de Cooperación Internacional; 2006: 88
    Google Scholar
  • 3 Terrazas F, Valdivia F. Spatial dynamics of in situ conservation: handling the genetic diversity of Andean tubers in mosaic systems. Plant Genet Resour Newsl 1998; 114: 9-15
    PubMedGoogle Scholar
  • 4 Gupta MP. 270 Plantas medicinales Iberoamericanas, 1ra edición. Bogotá: Presencia Ltda; 1995: 548-549
    Google Scholar
  • 5 Oblitas EP. Plantas medicinales de Bolivia, 1ra edición. Cochabamba: Los amigos del libro; 1993: 202
    Google Scholar
  • 6 Pérez E. Plantas útiles de Colombia. Ensayo de botánica colombiana aplicada, 1ra edición. Bogotá: Litografía Arco; 1978: 730
    Google Scholar
  • 7 Pérez AE. Plantas útiles de Colombia. Ensayo de botánica colombiana aplicada, 1ra edición. Bogotá: Imprenta Nacional; 1947
    Google Scholar
  • 8 Apaza TL, Rodríguez CM, Potente G, Rumbero SA. Anti-inflammatory potential of Macamides isolated from yellow tubers of Mashua (Tropaeolum tuberosum). Planta Med Int Open 2020; 7: e88-e99
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Apaza TL, Tena Pérez V, Serban AM, Alonso Navarro MJ, Rumbero A. Alkamides from Tropaeolum tuberosum inhibit inflammatory response induced by TNF-α and NF-κB. J Ethnopharmacol 2019; 235: 199-205
    CrossrefPubMedGoogle Scholar
  • 10 Hung CY, Tan CH. TRP Channels in nociception and pathological pain. Adv Exp Med Biol 2018; 1099: 13-27
    CrossrefPubMedGoogle Scholar
  • 11 Carey LM, Gutierrez T, Deng L, Lee WH, Mackie K, Hohmann AG. Inflammatory and neuropathic nociception is preserved in GPR55 knockout mice. Sci Rep 2017; 7: 944
    CrossrefPubMedGoogle Scholar
  • 12 Mickle AD, Shepherd AJ, Mohapatra DP. Nociceptive TRP channels: sensory detectors and transducers in multiple pain pathologies. Pharmaceuticals (Basel) 2016; 9: 72
    CrossrefPubMedGoogle Scholar
  • 13 Wang H, Cheng X, Tian J, Xiao Y, Tian T, Xu F, Hong X, Zhu MX. TRPC channels: Structure, function, regulation and recent advances in small molecular probes. Pharmacol Ther 2020; 209: 107497
    CrossrefPubMedGoogle Scholar
  • 14 Clapham DE. TRP channels as cellular sensors. Nature 2003; 426: 517-524
    CrossrefPubMedGoogle Scholar
  • 15 Frias B, Merighi A. Capsaicin, nociception and pain. Molecules 2016; 21: E797
    CrossrefPubMedGoogle Scholar
  • 16 Fattori V, Hohmann MS, Rossaneis AC, Pinho-Ribeiro FA, Verri WA. Capsaicin: Current understanding of its mechanisms and therapy of pain and other pre-clinical and clinical uses. Molecules 2016; 21: E844
    CrossrefPubMedGoogle Scholar
  • 17 Gunthorpe MJ, Chizh BA. Clinical development of TRPV1 antagonists: targeting a pivotal point in the pain pathway. Drug Discov Today 2009; 14: 56-67
    CrossrefPubMedGoogle Scholar
  • 18 Voight EA, Kort ME. Transient receptor potential vanilloid-1 antagonists: a survey of recent patent literature. Expert Opin Ther Pat 2010; 20: 1107-1122
    CrossrefPubMedGoogle Scholar
  • 19 Kyle DJ, Tafesse L. TRPV1 antagonists: a survey of recent patent literature. Expert Opin Ther Pat 2006; 16: 977-996
    CrossrefPubMedGoogle Scholar
  • 20 Rowbotham MC, Nothaft W, Duan WR, Wang Y, Faltynek C, McGaraughty S, Chu KL, Svensson P. Oral and cutaneous thermosensory profile of selective TRPV1 inhibition by ABT-102 in a randomized healthy volunteer trial. Pain 2011; 152: 1192-1200
    CrossrefPubMedGoogle Scholar
  • 21 Gavva NR, Treanor JJ, Garami A, Fang L, Surapaneni S, Akrami A, Alvarez F, Bak A, Darling M, Gore A, Jang GR, Kesslak JP, Ni L, Norman MH, Palluconi G, Rose MJ, Salfi M, Tan E, Romanovsky AA, Banfield C, Davar G. Pharmacological blockade of the vanilloid receptor TRPV1 elicits marked hyperthermia in humans. Pain 2008; 136: 202-210
    CrossrefPubMedGoogle Scholar
  • 22 Chizh BA, OʼDonnell MB, Napolitano A, Wang J, Brooke AC, Aylott MC, Bullman JN, Gray EJ, Lai RY, Williams PM, Appleby JM. The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans. Pain 2007; 132: 132-141
    CrossrefPubMedGoogle Scholar
  • 23 Tamayo N, Liao H, Stec MM, Wang X, Chakrabarti P, Retz D, Doherty EM, Surapaneni S, Tamir R, Bannon AW, Gavva NR, Noman MH. Design and synthesis of peripherally restricted transient receptor potential vanilloid 1 (TRPV1) antagonists. J Med Chem 2008; 51: 2744-2757
    CrossrefPubMedGoogle Scholar
  • 24 Stec MM, Bo Y, Chakrabarti PP, Liao L, Ncube M, Tamayo N, Tamir R, Gavva NR, Treanor JJ, Norman MH. Substituted aryl pyrimidines as potent and soluble TRPV1 antagonists. Bioorg Med Chem Lett 2008; 18: 5118-5122
    CrossrefPubMedGoogle Scholar
  • 25 Tafesse L, Sun Q, Schmid L, Valenzano KJ, Rotshteyn Y, Su X, Kyle DJ. Synthesis and evaluation of pyridazinylpiperazines as vanilloid receptor 1 antagonists. Bioorg Med Chem Lett 2004; 14: 5513-5519
    CrossrefPubMedGoogle Scholar
  • 26 Cortright DN, Krause JE, Broom DC. TRP channels and pain. Biochim Biophys Acta 2007; 1772: 978-988
    CrossrefPubMedGoogle Scholar
  • 27 Nilius B, Owsianik G, Voets T, Peters JA. Transient receptor potential cation channels in disease. Physiol Rev 2007; 87: 165-217
    CrossrefPubMedGoogle Scholar
  • 28 Nagy I, Santha P, Jancso G, Urban L. The role of the vanilloid (capsaicin) receptor (TRPV1) in physiology and pathology. Eur J Pharmacol 2004; 500: 351-369
    CrossrefPubMedGoogle Scholar
  • 29 Southall MD, Li T, Gharibova LS, Pei Y, Nicol GD, Travers JB. Activation of epidermal vanilloid receptor-1 induces release of proinflammatory mediators in human keratinocytes. J Pharmacol Exp Ther 2003; 304: 217-222
    CrossrefPubMedGoogle Scholar
  • 30 Pare M, Elde R, Mazurkiewicz JE, Smith AM, Rice FL. The Meissner corpuscle revised: a multiafferented mechanoreceptor with nociceptor immunochemical properties. J Neurosci 2001; 21: 7236-7246
    CrossrefPubMedGoogle Scholar
  • 31 Inoue K, Koizumi S, Fuziwara S, Denda S, Inoue K, Denda M. Functional vanilloid receptors in cultured normal human epidermal keratinocytes. Biochem Biophys Res Commun 2002; 291: 124-129
    CrossrefPubMedGoogle Scholar
  • 32 Henslee EA, Torcal Serrano RM, Labeed FH, Jabr RI, Fry CH, Hughes MP, Hoettges KF. Accurate quantification of apoptosis progression and toxicity using a dielectrophoretic approach. Analyst 2016; 141: 6408-6415
    CrossrefPubMedGoogle Scholar
  • 33 Chan FKM, Moriwaki K, De Rosa MJ. Detection of necrosis by release of lactate dehydrogenase activity. Methods Mol Biol 2013; 979: 65-70
    CrossrefPubMedGoogle Scholar
  • 34 Arnott JA, Planey SL. The influence of lipophilicity in drug discovery and design. Expert Opin Drug Discov 2012; 7: 863-875
    CrossrefPubMedGoogle Scholar
  • 35 Yang F, Zheng J. Understand spiciness: mechanism of TRPV1 channel activation by capsaicin. Protein Cell 2017; 8: 169-177
    CrossrefPubMedGoogle Scholar
  • 36 Walpole CSJ, Wrigglesworth R, Bevan S, Campbell EA, Dray A, James IF, Perkins MN, Reis DJ, Winter J. Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 3. The hydrophobic side-chain “C-region”. J Med Chem 1993; 36: 2381-2389
    CrossrefPubMedGoogle Scholar
  • 37 Walpole CSJ, Wrigglesworth R, Bevan S, Campbell EA, Dray A, James IF, Perkins MN, Reis DJ, Winter J. Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 3. The aromatic “A-region”. J Med Chem 1993; 36: 2362-2372
    CrossrefPubMedGoogle Scholar
  • 38 Walpole CSJ, Wrigglesworth R, Bevan S, Campbell EA, Dray A, James IF, Perkins MN, Reis DJ, Winter J. Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 3. The amide bond “B-region”. J Med Chem 1993; 36: 2373-2380
    CrossrefPubMedGoogle Scholar
  • 39 de la Rosa-Lugo V, Acevedo-Quiroz M, Déciga-Campos M, Rios MY. Antinociceptive effect of natural and synthetic alkamides involves TRPV1 receptors. J Pharm Pharmacol 2017; 69: 884-895
    CrossrefPubMedGoogle Scholar
  • 40 Chen X, Thibeault S. Effect of DMSO concentration, cell density and needle gauge on the viability of cryopreserved cells in three dimensional hyaluronan hydrogel. Conf Proc IEEE Eng Med Biol Soc 2013; 2013: 6228-6231
    PubMedGoogle Scholar
  • 41 Park CH, Martinez BC. Enhanced release of rosmarinic acid from Coleus blumei permeabilized by dimethyl sulfoxide (DMSO) while preserving cell viability and growth. Biotechnol Bioeng 1992; 40: 459-464
    CrossrefPubMedGoogle Scholar
  • 42 Koley D, Bard AJ. Triton X-100 concentration effects on membrane permeability of a single HeLa cell by scanning electrochemical microscopy (SECM). Proc Natl Acad Sci U S A 2010; 107: 16783-16787
    CrossrefPubMedGoogle Scholar
  • 43 Bruggisser R, von Daeniken K, Jundt G, Schaffner W, Tullberg-Reinert H. Interference of plant extracts, phytoestrogens and antioxidants with the MTT tetrazolium assay. Planta Med 2002; 68: 445-448
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Wu MH, Yung BY. Cell cycle phase-dependent cytotoxicity of actinomycin D in HeLa cells. Eur J Pharmacol 1994; 270: 203-212
    PubMedGoogle Scholar