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| ORIGINAL ARTICLE |
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| Year : 2017 | Volume
: 9
| Issue : 5 | Page : 1-4 |
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Antinociceptive and anti-inflammatory effects of triterpenes from Pluchea quitoc DC. aerial parts
Francisco Alcione Nobre da Silva1, Sônia Maria de Farias Freire1, Marilene Oliveira da Rocha Borges1, Francisco Erivaldo Vidal Barros1, Maria da Glória Teixeira de Sousa1, Maria Nilce de Sousa Ribeiro2, Giselle Maria Skelding Pinheiro Guilhon3, Adolfo Henrique Müller3, Antonio Carlos Romão Borges1
1 Department of Physiological Sciences, Federal University of Maranhão, University City, Bacanga, São Luís, Maranhão, Brazil
2 Department of Pharmacy, Federal University of Maranhão, University City, Bacanga, São Luís, Maranhão, Brazil
3 Department of Chemistry, Federal University of Pará, Pará, Brazil
| Date of Web Publication | 12-Dec-2017 |
Correspondence Address:
Antonio Carlos Romão Borges
Department of Physiological Sciences, Federal University of Maranhao, Avenue of the Portuguese, 1966, University City, Bacanga, 65080-805, Sao Luis, Maranhao
Brazil
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/pr.pr_51_17
 Abstract | | |
Background: Pluchea quitoc DC. (Asteraceae), a medicinal plant known as “quitoco,” “caculucage,” “tabacarana” and “madre-cravo,” is indicated for inflammatory conditions such as bronchitis, arthritis, and inflammation in the uterus and digestive system. Objective: This study evaluated the analgesic and anti-inflammatory activities of the triterpenes compounds obtained from P. quitoc aerial parts. Materials and Methods: The triterpenes compounds β-amyrin, taraxasterol and pseudo-taraxasterol in a mixture (T); β-amyrin, taraxasterol and pseudo-taraxasterol acetates in a mixture (Ta); β-amyrin, taraxasterol, pseudo-taraxasterol acetates in a mixture with β-amyrin, taraxasterol and pseudo-taraxasterol myristates (Tafe) were analyzed in the models of nociception and inflammation. The evaluation of antinociceptive activity was carried out by the acetic acid-induced writhing and tail-flick tests while leukocyte migration to the peritoneal cavity was used for anti-inflammatory profile. Results: The oral administration of T or Tafe (40 mg/kg and 70 mg/kg) and Ta (70 mg/kg) to mice reduced acetic acid-induced writhing. The tail-flick response of mice was not affected by T or Tafe (40 mg/kg). T or Tafe (40 mg/kg) and Ta (70 mg/kg) also inhibited peritoneal leukocyte infiltration following the injection of carrageenan. Conclusion: The results demonstrate the anti-inflammatory and peripheral antinociceptive activity of the triterpenes β-amyrin, taraxasterol, and pseudo-taraxasterol that were decreased when these were acetylated; while the acetylated triterpenes in mixture with myristyloxy triterpenes improved this activity. These compounds seem, at least in part, to be related to the plant's reported activity. Keywords: Anti-inflammatory, antinociceptive, Pluchea quitoc, triterpene
How to cite this article:
Nobre da Silva FA, de Farias Freire SM, da Rocha Borges MO, Vidal Barros FE, de Sousa Md, de Sousa Ribeiro MN, Pinheiro Guilhon GM, Müller AH, Romão Borges AC. Antinociceptive and anti-inflammatory effects of triterpenes from Pluchea quitoc DC. aerial parts. Phcog Res 2017;9, Suppl S1:1-4 |
How to cite this URL:
Nobre da Silva FA, de Farias Freire SM, da Rocha Borges MO, Vidal Barros FE, de Sousa Md, de Sousa Ribeiro MN, Pinheiro Guilhon GM, Müller AH, Romão Borges AC. Antinociceptive and anti-inflammatory effects of triterpenes from Pluchea quitoc DC. aerial parts. Phcog Res [serial online] 2017 [cited 2021 Mar 7];9, Suppl S1:1-4. Available from: http://www.phcogres.com/text.asp?2017/9/5/1/220639 |
Summary
The mixtures of hydroxylated, acetylated, and myristate triterpenes isolated from hexanic extracts of Pluchea quitoc DC. were analyzed in the models of nociception and inflammation in mice. The results demonstrate the anti-inflammatory and peripheral antinociceptive activity of the triterpenes β-amyrin, taraxasterol, and pseudo-taraxasterol. This study showed too that the activity of triterpenes may be decreased by their being acetylated, while the acetylated triterpenes in mixture with myristate triterpenes improved this activity.
Abbreviations Used: T: Triterpenes compounds β-amyrin, taraxasterol, and pseudo-taraxasterol in a mixture, Ta: Triterpenes compounds β-amyrin, taraxasterol and pseudo-taraxasterol acetates in a mixture, Tafe: Triterpenes compounds β-amyrin, taraxasterol, pseudo-taraxasterol acetates in a mixture with β-amyrin, taraxasterol and pseudo-taraxasterol myristates, Ctrl: Control, Indo: Indomethacin, Dexa: Dexamethasone, EtOAc: Ethyl acetate, MeOH: Methanol.
| Introduction | |  |
Pluchea quitoc DC., a medicinal plant used in folk medicine, like some other plants belonging to the same genus,[1],[2],[3],[4],[5] is an aromatic shrub of the Asteraceae family, popularly known in Brazil as “quitoco,” “madre-cravo,” “caculucage,” or “tabacarana.” It is used in traditional medicine for the treatment of inflammation as well as of digestive and respiratory diseases in the North and Central West of Brazil.[6],[7]
The phytochemical analysis of the less polar fractions of the hexane extract of this species afforded stigmasterol, a mixture of β-amyrin, taraxasterol and pseudo-taraxasterol, and six eudesmane derivatives such as cuauthemone [8] while more polar fractions yielded the such as cuauthemones and epoxycuauthemones.[9],[10] Casticin, a flavone, was isolated from the hexane extract of this species and has shown in vitro activity against the epimastigote forms of Trypanosoma cruzi.[11] The ethanolic extract from aerial parts of P. quitoc modulated the hematopoietic response during bacterial infection [12] and counteracted the tumor-induced myelopoietic suppression in Ehrlich ascites tumor-bearing mice.[13]
Experimental studies have demonstrated anti-inflammatory and antinociceptive activities of triterpenes β-amyrin and taraxasterol. It was determined the in vivo anti-arthritic effect of taraxasterol on arthritis induced by Freund's complete adjuvant in rats.[14] In vitro study demonstrated that taraxasterol inhibited IL-1 β-induced NO and PGE2 production, as well as MMP-1, MMP-3, MMP-13, iNOS, and COX-2 expression in chondrocytes and exhibited anti-inflammatory effects in IL-1 β-stimulated chondrocytes through the inhibition of NF-κB activation.[15] The triterpenes α and β-amyrin produced antinociceptive effect on rat model of orofacial pain induced by formalin or capsaicin.[16]
We have previously shown that the ethanolic extract of P. quitoc had anti-inflammatory and antinociceptive effects in mice and rats in various analgesic and inflammatory models.[17]
In this work, we evaluated the anti-inflammatory and antinociceptive effects of mixtures of hydroxylated, acetylated and myristate triterpenes isolated from hexanic extracts of P. quitoc in mice, to determine whether these compounds might be responsible for the plant's reported activity.
| Materials and Methods | | |
Plant materials
P. quitoc was collected at Peixe-Boi, Pará State, Brazil and identified by the botanist Dr. João Ubiratan Santos, from Museu Paraense Emílio Goeldi (Belém, Pará, Brazil) where a voucher specimen has been deposited (No. 147609).
Isolation of the compounds
The aerial parts of P. quitoc (7 kg) were air dried and extracted with hexane at room temperature. Part of the crude hexane extract (20 g) was subjected to chromatography on a silica gel column and eluted with solvents of increasing polarity in the order hexane, hexane- ethyl acetate (EtOAc), EtOAc, and MeOH. The fraction containing the esterified triterpenes (2257 mg) was obtained from 1% to 3% EtOAc in hexane and was submitted to further chromatography separation on a silica gel column eluted with mixtures of EtOAc in hexane 0.5% and 1% yielding 977 mg of a mixture of β-amyrin acetate (16.26%), taraxasterol acetate (21.35%), pseudo-taraxasterol acetate (5.33%) in mixture with β-amyrin myristate (16.26%), taraxasterol myristate (27.18%), pseudo-taraxasterol myristate (13.59%) (Tafe) and 313 mg of a mixture of β-amyrin acetate (16.66%), taraxasterol acetate (66.66%), and pseudo-taraxasterol acetate (16.66%) (Ta, 1:4:1). Part of the fraction Tafe was submitted to hydrolysis yielding the hydroxylated triterpenes β-amyrin, taraxasterol, and pseudo-taraxasterol and myristic acid, which structures were confirmed by 1H nuclear magnetic resonance (NMR),13C NMR, and gas chromatography-mass spectroscopy spectral analysis. The acetates of the triterpenes (Ta) were identified by comparison of their 13C NMR spectral data with those reported in the literature.[18],[19] The hydroxylated triterpenoid fractions were obtained from 5% to 10% EtOAc in hexane, yielding 127 mg of a mixture of β-amyrin (40.0%), taraxasterol (40.0%), and pseudo-taraxasterol (20.0%) (T, 1:1:0.5).[8],[9]
Animals
Swiss mice (25–30 g), obtained from the Animal House of Federal University of Maranhão, were used. Animals were maintained under environmental conditions and had free access to a standard diet and water ad libitum. All experimental protocols were developed in accordance with the principles of ethics and animal welfare designated by the Brazilian College of Animal Experiments (COBEA) and the ethical guidelines for the investigation of experimental pain in conscious animals.[20]
Antinociceptive activity
Acetic acid-induced writhing test
The writhing test described previously [21] was used with adaptations.[22],[23] T or Tafe (40 mg/kg and 70 mg/kg) and Ta (70 mg/kg) in 4% tween 80 and water (vehicle), indomethacin (10 mg/kg) or vehicle, were administered p. o. in mice (n = 5–9), 60 min before acetic acid (0.8% v/v, 0.1 ml/10 g). The response to intraperitoneal injection of acid was cumulatively counted for 20 min.
Tail-flick test
Experiments were carried out according to previously described methodology,[24] with modifications. Male and female Swiss mice (n = 5) were placed on the tail-flick unit (Ugo Basile) so that the tail occluded a slit over a photocell. The source of heat was applied by a 70-W lamp mounted in a reflector and adjusted to 55°C ± 2°C. When the animal moved its tail away from the slit light fell on the photocell, and the timer was automatically stopped. The apparatus was previously calibrated to produce tail-flick latencies of approximately 3–5 s in control animals. The mice were treated with vehicle, T or Tafe (40 mg/kg, p. o.), or morphine (20 mg/kg, s. c.). All mice were observed in control conditions (60 and 30 min before) and 30, 60, 90, 120, and 150 min after drug administration.
Anti-inflammatory activity
Carrageenan-induced peritonitis test
The acute carrageenan-induced inflammatory reaction was induced by modification of the technique previously described.[25] Male and female Swiss mice (n = 5) were pretreated with T or Tafe (40 mg/kg), Ta (70 mg/kg), dexamethasone (0.5 mg/kg) or vehicle, p. o., 30 min before the injection of carrageenan (0.25 ml, 1% w/v in saline), into the peritoneal cavity. Four hours after the application of the irritant agent, the mice were sacrificed by cervical dislocation. Ca ++ and Mg ++ free heparinized (10 IU/ml) phosphate-buffered saline (2 ml) was injected into the peritoneal cavity and after a gentle massage, peritoneal fluids were removed; total leukocytes were determined in a Neubauer chamber.
Statistical analysis
The data are expressed as means ± standard error of the mean for 5–9 animals per group. The statistical analysis between treatment groups was done by one-way analysis of variance followed by Newman–Keuls test. Comparison between individual groups was analyzed with Student's t-test. Results were considered statistically significant when P < 0.05.
| Results | | |
The triterpenes caused dose-dependent inhibition of the acetic acid-induced writhing response in mice [Figure 1]. In control animals treated with vehicle, the total number of writhing movements determined over 20 min was 22.6 ± 2.4 (n = 8). Pretreatment with T or Tafe (40 mg/kg and 70 mg/kg) inhibited the number of writhing by 68.2% and 98.9% or 58.5% and 91.2%, respectively, when compared with the control (P < 0.05). In comparison, indomethacin (10 mg/kg) reduced writhing movements by 63.8%. However, Ta (70 m/kg) returned an inhibition of only 30.8%. The tail-flick test demonstrated that the mice treated with T or Tafe (40 mg/kg, p. o.) did not present a longer latency than the control animals. In the same conditions, the tail-flick latency of mice treated with morphine (20 mg/kg, s. c.) was increased 92.3% after 30 min. In the experiment involving carrageenan-induced inflammation in the peritoneal cavity, the leukocyte migration in control mice treated with the vehicle was 4.11 × 106/mm 3 ± 0.23 [Figure 2]. Previous treatment p. o. with T or Tafe (40 mg/kg) or Ta (70 mg/kg) reduced the migration by 56.5%, 44.6%, and 43.1%, respectively (P < 0.05). The animals treated with dexamethasone, a steroidal agent used as a positive control, exhibited an inhibition by 63.3%. | Figure 1: Effects of oral treatment of mice with the vehicle (Ctrl), triterpene compounds-β-amyrin, taraxasterol, pseudo-taraxasterol in a mixture (T), β-amyrin, taraxasterol, pseudo-taraxasterol acetates in a mixture (Ta), β-amyrin, taraxasterol, pseudo-taraxasterol acetate in a mixture with β-amyrin, taraxasterol, pseudo-taraxasterol myristates (Tafe) extracted from Pluchea quitoc DC. aerial parts or indomethacin (Indo) on acetic acid-induced writhing. The vertical bars indicate the mean ± standard error of the mean. Of numbers of writhing movements. *P < 0.05 versus control (analysis of variance-Newman–Keuls test). †P < 0.05 versus 40 mg/kg (Student's t-test)
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 | Figure 2: Effects of oral treatment of mice with the vehicle (Ctrl), triterpene compounds-β-amyrin, taraxasterol, pseudo-taraxasterol in a mixture (T), β-amyrin, taraxasterol, pseudo-taraxasterol acetates in a mixture (Ta), β-amyrin, taraxasterol, pseudo-taraxasterol acetates in a mixture with β-amyrin, taraxasterol, pseudo-taraxasterol myristates (Tafe) extracted from Pluchea quitoc DC. aerial parts or dexamethasone (Dexa) on carrageenan-induced peritonitis. The vertical bars indicate the mean ± Standard Error of the Mean. of numbers of total leukocytes (leukocyte N × 106/mm3) of peritoneal wash. *P < 0.05 versus control (analysis of variance-Newman–Keuls test). †P < 0.05 versus T group (Student's t-test)
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| Discussion | | |
This study evaluated the antinociceptive and anti-inflammatory effects of a mixture of triterpenes from P. quitoc using different stimuli, including chemical agents (acetic acid, carrageenan) and heat (tail flick). The triterpenes β-amyrin, taraxasterol, and pseudo-taraxasterol in mixture, administered p. o. showed a significant and dose-dependent activity against the acetic acid-induced writhing response in mice and exhibited higher activity than the acetylated triterpenes (β-amyrin, taraxasterol, and pseudo-taraxasterol acetates); at the same dose (70 mg/kg), the effect of the former was 63 times higher. Nevertheless, the mixture of acetylated triterpenes with β-amyrin, taraxasterol and pseudo-taraxasterol myristates presented an effect comparable with that of the triterpenes. The hydroxylated triterpenes and acetylated triterpene with myristate triterpene were inactive in the mouse tail-flick model of analgesia, suggesting that these compounds have no central analgesic properties. In contrast, when mice were treated with the ethanolic extract of P. quitoc the response time was significantly prolonged by 44.1% after 30 min.[17] The ability of the triterpenes to reduce the number of writhing and to not prolong the time of response of the tail-flick reflex indicates that a peripheral mechanism is involved. The writhing response is thought to involve, in part, local peritoneal receptors while the tail-flick test response is essentially a spinal reflex.[26] It is possible that other compounds of the plant are responsible for this effect. The migration of leukocytes to the site of inflammation is a fundamental aspect of the inflammatory process. Cell migration is the result of many different processes including adhesion and cell mobility.[27] Intraperitoneal injection of carrageenan led to the recruitment of leukocytes to the inflammatory site. In this study, we compared the effect on cell migration of vehicle, dexamethasone, and the mixture of triterpenes. It has been reported that triterpenoids, a fraction containing cycloartenol as the main component, inhibited peritoneal leukocyte infiltration.[27] Here, similar to what was shown in the writhing test the acetoxyl group decreased the effect of triterpenes on leukocytes migration. The treatment of animals with Tafe (myristyloxy triterpenes with acetyloxy triterpene, 40 mg/kg), did not show a significant difference compared to treatment with T at the same dose. However, the treatment of animals with Ta (acetyloxy triterpene) at a dose 1.75 times higher (70 mg/kg) reduced the migration by 13.4% less than T (hydroxylated triterpenes, 40 mg/kg, P < 0.05), indicating higher hydroxylated triterpene activity. These results raise the possibility that the esterified triterpenes possess lower antinociceptive and anti-inflammatory properties, similar to the finding that naturally occurring palmitate lupeol decreased the anti-inflammatory activity comparatively less than triterpene lupeol.[28]In vitro studies investigating the effect of triterpenes isolated from Pluchea lanceolata under neuroinflammation conditions also demonstrated a higher effect of triterpene compared to acetyloxy triterpene.[29] This study showed the anti-inflammatory and peripheral antinociceptive activity of triterpenes β-amyrin, taraxasterol, and pseudo-taraxasterol, β-amyrin, taraxasterol and pseudo-taraxasterol acetates and β-amyrin, taraxasterol and pseudo-taraxasterol myristates in misture. This study showed too that the activity of triterpenes may be decreased by their being acetylated, while acetoxyled triterpenes in mixture with myristate triterpenes improved this activity.
| Conclusion | | |
The results demonstrate the anti-inflammatory and peripheral antinociceptive activities of the mixture of the triterpenes β-amirina, taraxasterol and pseudo-taraxasterol, that these activities were diminished in the mixture of triterpenes acetate, whereas these in mixture with triterpenos miristato improved these activities. These compounds appear, at least in part, to relate to the reported activity of the plant.
Financial support and sponsorship
The authors thank the Brazilian funding agencies CAPES, FINEP, CNPq, and FAPEMA for financial support.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
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