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Effects of Leontice smirnowii tuber monodesmosides and crude extract in carrageenan- and histamine-induced acute inflammation model of rats.

Abstract

Leontice smirnowii is a member of the Berberidaceae family. We have recently reported the 1,1-diphenyl-2-picryl-hydrazyl radical scavenging, superoxide anion radical scavenging, hydrogen peroxide scavenging, reducing power and metal chelating activities of L. smirnowii products. In the current study we investigated the possible effects of the crude extracts of L. smirnowii (CELS) and the monodesmoside's purified extract (MPE) of L. smirnowii in the carrageenan- and histamine-induced acute inflammation models in rats. The experiment revealed that CELS and MPE have anti-inflammatory effects, dose dependently in carrageenan-induced acute inflammation. On the other hand, their proinflammatory effects were surprisingly observed, especially in low doses, in the histamine-induced acute inflammation model. Summarizing these data, we may state that CELS and MPE exert their anti-inflammatory effects via non-histaminergic pathways.

[c] 2005 Elsevier GmbH. All rights reserved.

Keywords: Inflammation; Leontice smirnowii; Berberidaceae; Carrageenan; Histamine; Monodesmosides

Introduction

The majority of anti-inflammatory drugs have potent activity, but also they have various and severe adverse effects. Therefore, agents of natural origin with lower side effects are required as substitute chemical therapeutics (Verpoorte, 1999). The ethanolic extract of Leontice kiangnanensis found to inhibit the permeability of abdominal capillaries and the ear inflammation in mice as well as the swelling of hind paw and the proliferation of granuloma induced by cotton pellets in rats (Liu et al. 1991). Kalopanaxsaponin-A and -I (monodesmosides) exhibited significant antinociceptive effects on acetic acid-induced writhing and hot plate tests. On Freund's complete adjuvant reagent-induced rheumatoid arthritis in rats, Kalopanax-A and -I were reported to inhibit edema, agglutination and vascular permeability (Choi et al., 2002a). Kalopanax-A, was also found to inhibit cyclooxygenase (COX)-2 enzyme (Kim et al., 2002). We have recently tested the anti-inflammatory potential of alpha-hederin (monodesmo-side) and hederasaponin-C, hederacolchiside-E and hederacolchiside-F (bidesmosides) isolated from Hedera colchica in carrageenan-induced rat paw edema. Bidesmosides exerted anti-inflammatory potential (Gepdire-men et al., 2005). On the other hand, saponin products from Kalopanax pictus bark extracts were reported to show inhibition of adjuvant-induced arthritis in rats. (Li da et al., 2003). We have also recently reported the potent in vitro antioxidant activities of Leontice smirnowii products (Gulcin et al., in press). Considering these data, it was decided to test the possible anti-inflammatory effects of the crude extract of Leontice smirnowii (CELS) and the monodesmoside's purified extract of Leontice smirnowii (MPE) in the carrageenan- and histamine-induced acute inflammation models in rats.

Materials and methods

Plant material was collected in the Shiraki region of Georgia (07.2000) and dried in the shade. A voucher specimen is kept in the Department of Pharmacobotanic, Institute of Pharmacochemistry, Tbilisi, Georgia (Tubers no. 73700). Crushed tubers (500 g) were extracted with MeOH. After concentration, the aqueous layer was treated with BuOH to obtain a crude extract of saponins (100 g). The crude extract of saponins (200 mg) in 5% aqueous KOH (5 ml) was heated at 100[degrees]C in a sealed tube for 90 min. After neutralization with 10% HC1 (pH = 5), the prosapogenins (monodesmosides) were extracted with BuOH, 120 mg of light yellow powder of monodesmosides were obtained. Thin layer chromatographic (TLC) analysis of prosapogenins were performed using solvent systems: chloroform: methanol:water (26:14:3), developing with 25% sulfuric acid in methanol.

In total, 108 Wistar albino rats (n = 6 per group) weighing 140-180 g were used. They were fed on standard chow and tap water, kept at a room temperature of 22[degrees]C with a 12 h light/dark cycle. The University ethics committee approved the procedures.

Four different doses of (0.1, 1, 5 and 10 mg/kg) CELS and three different doses of MPE (0.1, 1, and 5 mg/kg) and indomethacin at a dose of 20 mg/kg were administrated to rats orally through the feeding tube. The same amount of water was given in same procedures for control group. The solvents were prepared to achieve the desirable dose in 1 ml of water. At 1 h after sample administration, edema was induced by subcutaneously injecting 0.1 ml of 1% carrageenan into the plantar side of the right hind paw. The paw volume was measured using a plethysmometer; before injection and 4 times at 1 h intervals (Birch et al., 1992), the obtained data receiving CELS and MPE were compared with indomethacin and control groups. The same experiment was conducted using 0.05 ml of 1% histamine, measured before injection and 4 times at 30min intervals. The results were compared with indomethacin and control groups.

The results are expressed as mean[+ or -]SEM. Independent samples-t test and analysis of the variance (ANOVA) were used for the evaluation of data. Probability of p<0.05 was considered significant.

Results

Indomethacin was found effective in all periods of carrageenan inflammation. In histamine-induced acute paw edema, indomethacin became effective at the period of 120 min. CELS and MPE have anti-inflammatory effects in carageenan-induced acute inflammation, dose dependently and proinflammatory in histamine inflammation, in small doses. Both compounds were not able to block histamine-induced paw edema. The smallest doses of CELS and MPE were found to have highest anti-inflammatory profile; they decreased edema instantly after 1 h of carrageenan injection and kept it that way until the last measurement. Five mg/kg of CELS was also found effective in all measurement periods of carrageenan inflammation. The highest dose of CELS started to exert anti-inflammatory activity after 2h of carageenan injection and extend until the last measurement. For further information, please refer to Tables 1 and 2.

Discussion

CELS and MPE exhibited the anti-inflammatory effects in carrageenan model. With respect to 20 mg/kg indomethacin, very small doses of CELS and MPE have significant anti-inflammatory effects. In the carrageenan model, the early phase (1-2 h) is mainly mediated by histamine, serotonin and the increase of prostaglandin (PG) synthesis in the surroundings of the damaged tissues (Vinegar et al., 1987), while the late phase is mainly mediated by bradykinin, leukotrienes, polymorphonuclear cells and PGs produced in tissue macrophages (Antonio and Souza Brito, 1998). In this experiment, the suppression of inflammation at the early phase can be contributed by histamine, serotonin and PG synthesis inhibition, while at the late phase by PG, especially bradykinin and leukotrienes synthesis inhibition. According to the results, statistical significance of the CELS and MPE are almost the same in the present study, which lead us to the statement that monodesmosides are the main active components exhibiting anti-inflammatory effect.

In the histamine-induced acute inflammation, the extracts of CELS and MPE of L. smirnowii showed proinflammatory effects, especially in small doses. The effects of histamine are outward passage of plasma protein and fluid into the extracellular spaces, an increase in the flow of lymph and protein content and formation of edema. [H.sub.1] receptors are clearly important for this response. Increased permeability results mainly from actions of histamine on postcapillary venules, where histamine causes the endothelial cells to contract and separate at their boundaries (Goodman-Gilman, 1990) by mediating mostly the [H.sub.1] receptors. In the light of these data, we may suggest that anti-inflammatory effects of CELS and MPE are mainly the result of mediating non-histaminergic pathways, which are mostly blocking the synthesis of serotonin, bradykinin, leukotrienes and/or polymorphonuclear cells. On the contrary, a proinflammatory effect may occur by activation of histaminergic pathways by these compounds.

Kalopanaxsaponin-A was found to significantly decrease malondialdehyde formation and the activities of xanthine oxidase and aldehyde oxidase in Freund's complete adjuvant arthritis model in rats. In addition, increased activity levels of superoxide dismutase, catalase and glutathione peroxidase were also reported (Choi et al., 2002b). We have also presented the antioxidant profiles of L. smirnowii extracts (Gulcin et al., in press). In the present study, the monodesmoside content of L. smirnowii extract's antioxidant properties may be responsible for their anti-inflammatory effect.

The results of the current study showed that CELS and MPE extracts are potent inhibitors of carrageenan-induced inflammation and they may exert their anti-inflammatory effects by mediating several pathways except histamine.

Acknowledgements

Dr. Kakhi Bakuridze was supported by a grant received from the TUBITAK-NATO-PC A2 program.

References

Antonio, M.A., Souza Brito, A.R., 1998. Oral anti-inflammatory and anti-ulcerogenic activities of a hydroalcoholic extract and partitioned fractions of Turnera ulmifolia. J. Ethnopharmacol. 61, 215-228.

Birch, P.J., Harrison, S.M., Hayes, A.G., Rogers, H., Tyers, M.B., 1992. The non-peptide NK1 receptor antagonist, (+/-)-CP-96,345, produces antinociceptive and anti-edema effects in the rat. Br. J. Pharmacol. 105, 508-510.

Choi, J., Huh, K., Kim, S.H., Lee, K.T., Park, H.J., Han, Y.N., 2002a. Antinociceptive and anti-rheumatoidal effects of Kalopanax pictus extract and its saponin components in experimental animals. J. Ethnopharmacol. 792, 199-204.

Choi, J., Huh, K., Kim, S.H., Lee, K.T., Lee, H.K., Park, H.J., 2002b. Kalopanaxsaponin A from Kalopanax pictus, a potent antioxidant in the rheumatoidal rat treated with Freund's complete adjuvant reagent. J. Ethnopharmacol. 79, 113-118.

Gepdiremen, A., Mshvildadze, V., Suleyman, H., Elias, R., 2005. Acute anti-inflammatory activity of four saponins isolated from ivy: alpha-hederin, hederasaponin-C, hederacolchiside-E and hederacolchiside-F in carrageenan-induced rat paw edema. Phytomedicine 12, 440-444.

Goodman-Gilman, A., 1990. In: Hardman, J.G., Limbird, L.E. (Eds.), The Pharmacological Basis of Theraputics, 10th ed. McGraw Medical Publishing Division, USA, pp. 575-582.

Gulcin, I., Mshvildadze, V., Gepdiremen, A., Elias, R., in press. Screening of antiradical and antioxidant activity of monodesmosides and crude extract from Leontice smirnowii tuber. Phytomedicine.

Kim, Y.K., Kim, R.G., Park, S.J., Ha, J.H., Choi, J.W., Park, H.J., Lee, K.T., 2002. In vitro antiinflammatory activity of kalopanaxsaponin A isolated from Kalopanax pictus in murine macrophage RAW 264.7 cells. Biol. Pharmaceut. Bull. 25, 472-476.

Li da, W., Hyun, J.E., Jeong, C.S., Kim, Y.S., Lee, E.B., 2003. Antiinflammatory activity of alpha-hederin methyl ester from the alkaline hydrolysate of the butanol fraction of Kalopanax pictus bark extract. Biol. Pharmaceut. Bull. 26, 429-433.

Liu, Q., Zhu, G., Huang, P., 1991. Anti-inflammatory, analgesic and sedative effects of Leontice kiangnanensis P.L. Chiu. Zhongguo Zhong Yao Za Zhi 161, 50-53.

Verpoorte, R., 1999. Exploration of nature's chemodiversity: the role of secondary metabolites as leads in drug development. Drug Discov. Today 3, 232-238.

Vinegar, R., Truax, J.F., Selph, J.H., Johnsstone, P.R., Venable, A.L., Mckenzie, K.K., 1987. Pathway to carrageenan-induced inflammation in the hind limb of the rat. Fed. Proc. 6, 118-126.

A. Gepdiremen (a,*), V. Mshvildadze (b), K. Bakuridze (c), R. Elias (d)

(a) Faculty of Medicine, Department of Pharmacology, Ondokuz Mayis University, TR-55139-Kurupelit Samsun, Turkey

(b) Institue of Pharmacochemistry, Academy of Sciences of Georgia 36, st. P. Sarajishvili, 380059-Tbilisi, Goergia

(c) Department of Pharmacology, Tbilisi State Medical University, P. Sarajishvili, Tbilisi, Georgia

(d) Laboratory of Pharmacognosy and Homeopathy, Pharmacy Faculty of Mediterranean University, 13385 Marseille, France

*Corresponding author. Tel.: +90 36231219192294; fax: +90 3624576041.

E-mail address: akcahang@omu.edu.tr (A. Gepdiremen).
Table 1. The effects of CELS (crude extract of Leontice smirnowii) and
MPE (monodismosides purified extract) of Leontice smirnowii in
subsequent doses and indomethacin (Indomet.) in carrageenan-induced
acute paw edema (anti-inflammatory effect)

 Dose
 (mg/kg % Right paw volume reduction
Drugs wt.) n 1h 2h

Vehicle 6 47.0 [+ or -] 6.0 80.5 [+ or -] 8.6
Indomet. 20 6 26.3 [+ or -] 9.9* 42.9 [+ or -] 7.0***
CELS 0.1 6 13.2 [+ or -] 5.0**** 40.7 [+ or -] 7.9***
CELS 1 6 37.2 [+ or -] 7.6 75.0 [+ or -] 14.8
CELS 5 6 22.0 [+ or -] 3.0*** 45.7 [+ or -] 6.3**
CELS 10 6 23.5 [+ or -] 11.3 55.0 [+ or -] 13.3
MPE 0.1 6 17.0 [+ or -] 2.75**** 51.3 [+ or -] 8.0*
MPE 1 6 33.5 [+ or -] 11.1 60.9 [+ or -] 17.6
MPE 5 6 38.0 [+ or -] 2.7 64.4 [+ or -] 14.25

 % Right paw volume reduction
Drugs 3h 4h

Vehicle 96.55 [+ or -] 10.8 92.6 [+ or -] 9.9
Indomet. 51.2 [+ or -] 7.2*** 46.6 [+ or -] 6.9****
CELS 54.5 [+ or -] 9.4** 50.17 [+ or -] 9.6**
CELS 83.3 [+ or -] 8.7 76.0 [+ or -] 7.7
CELS 61.3 [+ or -] 6.3* 60.8 [+ or -] 5.1*
CELS 59.0 [+ or -] 13.7* 39.5 [+ or -] 12.6**
MPE 55.7 [+ or -] 9.7* 49.7 [+ or -] 7.9***
MPE 89.8 [+ or -] 16.5 80.3 [+ or -] 17.0
MPE 81.4 [+ or -] 15.6 65.4 [+ or -] 15.6

*<0.05, **p<0.01, ***p<0.005, ****p<0.001.

Table 2. The effects of CELS (crude extract of Leontice smirnowii) and
MPE (monodismosides purified extract) of Leontice smirnowii in
subsequent doses and indomethacin (Indomet.) in histamine-induced acute
paw edema. (proinflammatory effect)

 Dose
 (mg/kg % Right paw volume reduction
Drugs body wt.) n 30 min 60 min

Vehicle 6 27.2 [+ or -] 3.9 21.3 [+ or -] 4.4
Indomet. 20 6 26.8 [+ or -] 5.2 24.5 [+ or -] 3.9
CELS 0.1 6 50.3 [+ or -] 8.3 (#) 42.5 [+ or -] 8.2 (#)
CELS 1 6 36.6 [+ or -] 4.0 36.8 [+ or -] 5.1 (#)
CELS 5 6 36.5 [+ or -] 4.7 35.8 [+ or -] 4.8 (#)
CELS 10 6 22.3 [+ or -] 6.9 27.2 [+ or -] 4.8
MPE 0.1 6 53.8 [+ or -] 8.2 (#) 62.8 [+ or -] 8.9 (###)
MPE 1 6 45.2 [+ or -] 5.9 (###) 41.2 [+ or -] 4.7 (#)
MPE 5 6 44.0 [+ or -] 7.7 32.3 [+ or -] 8.1

 % Right paw volume reduction
Drugs 90 min 120 min

Vehicle 15.8 [+ or -] 4.4 20.6 [+ or -] 3.9
Indomet. 17.6 [+ or -] 4.4 10.0 [+ or -] 3.6
CELS 58.5 [+ or -] 7.4 (####) 46.3 [+ or -] 7.8 (#)
CELS 32.6 [+ or -] 3.2 (#) 29.0 [+ or -] 6.0
CELS 21.8 [+ or -] 6.18 24.6 [+ or -] 4.7
CELS 22.16 [+ or -] 6.4 24.5 [+ or -] 7.4
MPE 55.8 [+ or -] 4.2 (####) 43.2 [+ or -] 8.0 (#)
MPE 32.0 [+ or -] 5.6 (#) 29.6 [+ or -] 6.9
MPE 29.2 [+ or -] 8.1 29.6 [+ or -] 7.4

(#) p<0.05, (##) p<0.01, (###) p<0.005, (####) p<0.001.
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Title Annotation:SHORT COMMUNICATION
Author:Gepdiremen, A.; Mshvildadze, V.; Bakuridze, K.; Elias, R.
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Geographic Code:1U5GA
Date:Nov 1, 2006
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