A New Naphthoquinone Isolated from the Bulbs of Cipura paludosa and Pharmacological Activity of Two Main Constituents

Abstract

Cipura paludosa (Iridaceae) is a plant that is distributed in the north region of Brazil. Its bulbs are used in folk medicine to treat inflammation and pain. Four naphthalene derivatives have been isolated from the bulbs of this plant. Three of them have been identified as the known naphthalene derivatives, eleutherine, iso-eleutherine, and hongkonin. The structure of the fourth and new component was determined as 11-hydroxyeleutherine by extensive NMR study. In addition, the in vivo effect of the two major compounds, eleutherine and iso-eleutherine, was evaluated in carrageenan-induced hypernociception and inflammation in mice. Eleutherine and iso-eleutherine (1.04–34.92 µmol/kg), dosed intraperitoneally (i. p.) or orally (p. o.), decreased the carrageenan-induced paw oedema (i. p. – inhibitions of 36 ± 7 % and 58 ± 14 %, respectively; p. o. – inhibitions of 36 ± 7 % and 58 ± 14 %, respectively). Iso-eleutherine, but not eleutherine, significantly reduced (inhibitions of 39 ± 4 %) the plasma extravasation induced by intradermal (i. d.) injection of carrageenan. Likewise, eleutherine and iso-eleutherine (1.04–34.92 µmol/kg, i. p. or p. o.) were also effective in preventing the carrageenan-induced hypernociceptive response (i. p. – inhibition of 59 ± 4 % and 63 ± 1 %, respectively; p. o. – inhibitions of 36 ± 7 % and 58 ± 14 %, respectively). It was also suggested that the anti-inflammatory and anti-hypernociceptive effects of eleutherine or iso-eleutherine partly depend on the interference with the synthesis or activity of mast cell products, kinins, cytokine, chemokines, prostanoids, or sympathetic amines. Our findings show that two major compounds of C. paludosa contain pharmacologically active constituents that possess antinociceptive and anti-inflammatory activity, justifying, at least in part, its popular therapeutic use for treating conditions associated with pain.

Cipura paludosa - Iridaceae - naphthalene derivatives - 11‐hydroxy‐eleutherine - inflammation - hypernociception

References

• 1 Calixto J B. Efficacy, safety, quality control, marketing and regulatory guidelines for herbal medicines (phytotherapeutic agents).  Braz J Med Biol Res. 2000;  33 179-189
• 2 Strohl W. The role of natural products in a modern drug discovery program.  Drug Discov Today. 2000;  5 39-41
• 3 Molinari G. Natural products in drug discovery: present status and perspectives.  Adv Exp Med Biol. 2009;  655 13-27
• 4 Cheng K W, Wong C C, Wang M, He Q Y, Chen F. Identification and characterization of molecular targets of natural products by mass spectrometry.  Mass Spectrom Rev. 2010;  29 126-155
• 5 Calixto J B, Beirith A, Ferreira J, Santos A R, Cechinel Filho V, Yunes R A. Naturally occurring antinociceptive substances from plants.  Phytother Res. 2000;  14 401-418
• 6 Quintão N L, da Silva G F, Antonialli C S, de Campos-Buzzi F, Corrêa R, Cechinel Filho V. N-antipyrine-3,4-dichloromaleimide, an effective cyclic imide for the treatment of chronic pain: the role of the glutamatergic system.  Anesth Analg. 2010;  110 942-950
• 7 Ding Y, Liang C, Kim J H, Lee Y M, Hyun J H, Kang H K, Kim J A, Min B S, Kim Y H. Triterpene compounds isolated from Acer mandshuricum and their anti-inflammatory activity.  Bioorg Med Chem Lett. 2010;  20 1528-1531
• 8 Goldblatt P. Iridaceae [with contributions from J.C. Manning and P. Rudall]. Kubitski K Families and genera of flowering plants, Vol. 2. Heidelberg; Springer Verlag 1998: 295-335
• 9 Lucena G M, Franco J L, Ribas C M, Azevedo M S, Meotti F C, Gadotti V M, Dafre A L, Santos A R, Farina M. Cipura paludosa extract prevents methyl mercury-induced neurotoxicity in mice.  Basic Clin Pharmacol Toxicol. 2007;  101 127-131
• 10 Lucena G M, Gadotti V M, Maffi L C, Silva G S, Azevedo M S, Santos A R. Antinociceptive and anti-inflammatory properties from the bulbs of Cipura paludosa Aubl.  J Ethnopharmacol. 2007;  112 19-25
• 11 Lucena G M, Porto F A, Campos E G, Azevedo M S, Cechinel Filho V, Prediger R D S, Ferreira V M. Cipura paludosa attenuates long-term behavioral deficits in rats exposed to methylmercury during early development.  Ecotoxicol Environ Saf. 2010;  73 1150-1158
• 12 Shibuya H, Fukushima T, Ohashi K, Nakamura A, Riswan S, Kitaka I. Indonesian medicinal plants. XX. Chemical structures of eleuthosides A, B and C, three new aromatic glucodides from the bulbs of Eleutherine palmifolia (Iridaceae).  Chem Pharm Bull. 1997;  45 1130-1134
• 13 Cheng Z, Huizu H, Wang C, Li Y, Ding J, Sankawa U, Noguchi H, Yoichi L H. Hongconin, a new naphthalene derivative from Hong-Cong, the rhizome of Eleutherine americana (Iridaceae).  Chem Pharm Bull. 1986;  34 2743-2746
• 14 Quintão N L M, Medeiros R, Santos A R S, Campos M M, Calixto J B. Effects of diacerhein on mechanical allodynia in inflammatory and neuropathic models of nociception in mice.  Anesth Analg. 2005;  101 1763-1769
• 15 Santodomingo-Garzón T, Cunha T M, Verri Jr W A, Valério D A, Parada C A, Poole S, Ferreira S H, Cunha F Q. Atorvastatin inhibits inflammatory hypernociception.  Br J Pharmacol. 2006;  149 14-22
• 16 Fernandes E S, Passos G F, Medeiros R, da Cunha F M, Ferreira J, Campos M M, Pianowski L F, Calixto J B. Anti-inflammatory effects of compounds alpha-humulene and (−)-trans-caryophyllene isolated from the essential oil of Cordia verbenacea.  Eur J Pharmacol. 2007;  569 228-236
• 17 Santos A R S, Miguel O G, Yunes R A, Calixto J B. Antinociceptive properties of the new alkaloid, cis-8,10-di-N-propyllobelidiol hydrochloride dihydrate isolated from Siphocampylus verticillatus: evidence for the mechanism of action.  J Pharmacol Exp Ther. 1999;  289 417-426
• 18 Komura H, Mizukawa K, Minakata H, Huizu H, Qin G, Xu R. New anthraquinones from Eleutherine americana.  Chem Pharm Bull. 1983;  31 4206-4208
• 19 Hara H, Maruyama N, Yamashita S, Hayashi Y, Lee K H, Bastow K F, Chairul R M, Imakura Y. Elecanacin, a novel naphthaquinone from the bulb of Eleutherine americana.  Chem Pharm Bull. 1997;  45 1714-1716
• 20 Han A R, Min H Y, Nam J W, Lee N Y, Wiryawan A, Suprapto W, Lee S K, Lee K R, Seo E K. Identification of a new naphthalene and its derivatives from the bulb of Eleutherine americana with inhibitory activity on lipopolysacharide-induced nitric oxide production.  Chem Pharm Bull. 2008;  56 1314-1316
• 21 Ifesan B O, Hamtasin C, Mahabusarakam W, Voravuthikunchai S P. Assessment of antistaphylococcal activity of partially purified fractions and pure compounds from Eleutherine americana.  J Food Prot. 2009;  72 354-359
• 22 Di Rosa M, Giroud J P, Willoughby D A. Studies on the mediators of the acute inflammatory response induced in rats in different sites by carrageenan and turpentine.  J Pathol. 1971;  104 15-29
• 23 Hong J H, Yu E S, Han A R, Nam J W, Seo E K, Hwang E S. Isoeleutherin and eleutherinol, naturally occurring selective modulators of Th cell-mediated immune responses.  Biochem Biophys Res Commun. 2008;  371 278-282
• 24 Mosmann T R, Bond M W, Coffman R L, Ohara J, Paul W E. T-cell and mast cell lines respond to B-cell stimulatory factor 1.  Proc Natl Acad Sci USA. 1986;  8 5654-5658
• 25 Cher D J, Mosmann T R. Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH1 clones.  J Immunol. 1987;  138 3688-3694
• 26 Song S H, Min H Y, Han A R, Nam J W, Seo E K, Seoung W P, Sang H L, Sang K L. Suppression of inducible nitric oxide synthase by (−)-isoeleutherin from the bulbs of Eleutherine americana through the regulation of NF-kappaB activity.  Int Immunopharmacol. 2009;  9 298-302
• 27 Cunha T M, Verri Jr W A, Silva J S, Poole S, Cunha F Q, Ferreira S H. A cascade of cytokines mediates mechanical inflammatory hypernociception in mice.  Proc Natl Acad Sci USA. 2005;  102 1755-1760
• 28 Cunha T M, Verri Jr W A, Fukada S Y, Guerrero A T, Santodomingo-Garzón T, Poole S, Parada C A, Ferreira S H, Cunha F Q. TNF-alpha and IL-1beta mediate inflammatory hypernociception in mice triggered by B1 but not B2 kinin receptor.  Eur J Pharmacol. 2007;  573 221-229
• 29 Verri Jr W A, Cunha T M, Parada C A, Poole S, Cunha F Q, Ferreira S H. Hypernociceptive role of cytokines and chemokines: targets for analgesic drug development?.  Pharmacol Ther. 2006;  112 116-138
• 30 Khasar S G, McCarter G, Levine J D. Epinephrine produces a beta-adrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of rat nociceptors.  J Neurophysiol. 1999;  81 1104-1112