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Effects of Constituents from the Bark of Magnolia Obovata on Nitric Oxide Production in Lipopolysaccharide-Activated Macrophages

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Effects of Constituents from the Bark of Magnolia Obovata on Nitric Oxide Production in Lipopolysaccharide-Activated Macrophages 716 Chem. Pharm. Bull. 49(6) 716—720 (2001) Vol. 49, No. 6 Effects of Constituents from the Bark of Magnolia obovata on Nitric Oxide Production in Lipopolysaccharide-Activated Macrophages Hisashi MATSUDA, Tadashi KAGEURA, Mamiko ODA, Toshio MORIKAWA, Yasuko SAKAMOTO, and Masayuki YOSHIKAWA* Kyoto Pharmaceutical University, Misasagi, Yamashina-ku, Kyoto 607–8412, Japan. Received January 12, 2001; accepted February 21, 2001 The methanolic extract from a Japanese herbal medicine, the bark of Magnolia obovata, was found to in- hibit nitric oxide (NO) production in lipopolysaccharide (LPS)-activated macrophages. By bioassay-guided sepa- ration, three neolignans (magnolol, honokiol, obovatol) and three sesquiterpenes (a-eudesmol, b -eudesmol, g-eu- desmol) were obtained as active constituents. A trineolignan (magnolianin), a phenylpropanoid glycoside (sy- ringin), lignan glycosides (liriodendrin, (1)-syringaresinol 49-O-b -D-glucopyranoside) and a sesquiterpene (caryophyllene oxide) did not show any activity. On the other hand, sesquiterpene-neolignans (eudesmagnolol, clovanemagnolol, caryolanemagnolol, eudeshonokiol A, eudesobovatol A) showed the strong cytotoxic effects. Ac- tive constituents (magnolol, honokiol, obovatol) showed weak inhibition for inducible NO synthase (iNOS) en- zyme activity, but potent inhibition of iNOS induction and activation of nuclear factor-kB. Key words Magnolia obovata; neolignan; nitric oxide; inducible nitric oxide synthase; nuclear factor-kB; inhibitor Inducible nitric oxide synthase (iNOS) is involved in the effects of the constituents from the bark of M. obovata on pathological processes related to overproduction of nitric NO production in LPS-stimulated macrophages. In addition, oxide (NO), and is expressed in response to pro-inflamma- we describe the effects of principal active neolignan con- tory agents such as interleukin (IL)-1b, tumor necrosis factor stituents [magnolol (1), honokiol (2), obovatol (3)] on iNOS (TNF)-a and lipopolysaccharide (LPS) in various cell types enzyme activity, induction of iNOS, and activation of NF-kB including macrophages, endothelial cells, and smooth muscle to clarify their action mechanisms. cells.1) Nuclear factor (NF)-kB is a major transcription factor involved in iNOS, TNF-a, IL-1b, and IL-8 genes expression. Results and Discussion NF-kB activation involves dissociation of an inhibitory sub- Isolation of Chemical Constituents from the Dried unit, IkB, which keeps NF-kB in the cytoplasm, thereby pre- Bark of M. obovata The bark of Japanese M. obovata was venting activation of the target gene in the nucleus. Cellular extracted with methanol under reflux. The methanolic extract signals lead to phosphorylation of IkB following elimination was subjected to ordinary- and reversed-phase silica gel col- of IkB from NF-kB by proteolytic degradation. Then, the ac- umn chromatography and finally HPLC to furnish five ne- tivated-NF-kB is released and translocated into the nucleus olignans, magnolol (1,13) 2.1% from the natural medicine), to activate transcription of its target genes.2) Inhibition of honokiol (2,14) 0.43%), obovatol (3,15) 0.26%), 4-O-methyl- iNOS enzyme activity or iNOS induction and inhibition of honokiol (4,16) 0.0031%), and 69-O-methylhonokiol (5,10,16) NF-kB activation may be of therapeutic benefit in various 0.0031%), seven sesquiterpene-neolignans, eudesmagnolol types of inflammation.2,3) (6,17) 0.096%), clovanemagnolol (7,18) 0.0061%), caryolane- Magnoliae Cortex, the dried bark of Magnolia (M.) obo- magnolol (8,10) 0.0044%), eudeshonokiols A (9,10) 0.0056%) 10) 19) vata THUNBERG and M. officinalis REHDER et WILSON, has been and B (10, 0.0054%), eudesobovatols A (11, 0.043%) used for treatment of gastrointestinal disorders, anxiety and and B (12,19) 0.024%), a trineolignan, magnolianin (13,20) allergic diseases including bronchial asthma in Japanese and 0.27%), a phenylpropanoid glycoside, syringin (14,21) 0.39%), Chinese traditional medicines. There have been many phar- two lignan glycosides, liriodendrin (15,22) 0.15%) and (1)- 23) macological reports of the activities of extracts or con- syringaresinol 49-O-b-D-glucopyranoside (16, 0.029%), and stituents from the bark of M. obovata or M. officinalis such four sesquiterpenes, caryophyllene oxide (17,24) 0.0049%), as muscle relaxation,4) central depressant effect,5) anti-gastric a-eudesmol (18,11g,24) 0.096%), b-eudesmol (19,11g,25) ulcer,6) vasorelaxant,7) antiallergic,8) antibacterial,9) and neu- 0.061%), and g-eudesmol (20,11g,26) 0.030%). rite spouting activities.10) In the course of our studies on con- Effects on NO Production First, the effects of neolig- stituents with NO production inhibitory activity from natural nans (1—5), sesquiterpene-neolignans (6—12) and ses- medicines,11) the methanolic extract from the dried bark of quiterpenes (17) isolated from the methanolic extract on ni- 2 M. obovata was found to inhibit nitrite (NO2 , a product of trite accumulation from LPS-activated macrophages were ex- NO) accumulation in LPS-activated mouse macrophages amined. Nitrite, an oxidative product of NO, was accumu- 5 (IC50 25 mg/ml). lated in the medium after 20-h of incubation with LPS. Ni- Previous reports demonstrated that two neolignans [mag- trite concentration in the medium without inhibitors (control nolol (1), honokiol (2)] showed inhibitory effects on NO pro- group) was 36.969.5 m M, and that in the medium without 12) duction from LPS-activated RAW 264.7 cells. However, ef- LPS (unstimulated group) was 0.460.8 m M (mean6S.D. of fects of other constituents on NO production from LPS-acti- 18 experiments). IC50 of reference compounds [caffeic acid vated mouse macrophages and their cytotoxicities for phenethyl ester (CAPE, an inhibitor of NF-kB activation),3b) G macrophages have not been examined. This report describes N -monomethyl-L-arginine (L-NMMA, a non-selective in- ∗ To whom correspondence should be addressed. e-mail: [email protected] © 2001 Pharmaceutical Society of Japan June 2001 717 Chart 1 hibitor of NOS),27) and guanidinoethyldisulfide (GED, an in- nan (1—3) reduced the activity, although the detailed struc- 28) 11g) hibitor of iNOS) ] were 4.0, 28, and 1.4 m M, respectively. ture–activity relationships still have to be clarified. Three neolignans [magnolol (1), honokiol (2), obovatol (3)] Eudesmols (18—20) did not show any cytotoxic effect, 5 inhibited the LPS-induced NO production (IC50 21— and neolignans (1—3) showed cytotoxic effects only at 34 m M). 4-O-Methylhonokiol (4) and 69-O-methylhonokiol 100 m M. However, cytotoxic effects of sesquiterpene-neolig- (5) showed less activity than 2. Eudesmagnolol (6), clovane- nan constituents (6—9, 11) were observed at lower concen- magnolol (7), caryolanemagnolol (8), eudeshonokiols A (9) trations in the MTT assay. and B (10), and eudesobovatols A (11) and B (12) showed Effects of 1—3 on iNOS Enzyme Activity, iNOS Protein the inhibition due to their cytotoxic effects. Magnolianin Induction, and NF-kB Activation Next, the effects of (13), syringin (14), liriodendrin (15), (1)-syringaresinol 49- three active constituents (1—3) on iNOS enzyme activity and O-b-D-glucopyranoside (16), and caryophyllene oxide (17) iNOS induction were examined. A reference compound, L- had no effect. In our previous study of NO production in- NMMA, inhibited iNOS enzyme activity with an IC50 of hibitors from the leaves of Laurus nobilis, three sesquiter- 13 m M, but 1—3 showed weak inhibition for iNOS activity; pene constituents [a-eudesmol (18), b-eudesmol (19), and g- inhibitory effects of 1, 2, and 3 at 100 m M were 16, 18, and eudesmol (20)] were found to show the activity. Under the 6%, respectively. iNOS was detected at 130 kDa after a 12-h same conditions, their IC50 values were 37, 44, and 53 m M, incubation with LPS by sodium dodecylsulfate–polyacry- respectively.11g) These results indicated that the conjugation lamide gel electrophoresis (SDS-PAGE)–Western blotting of methyl or sesquiterpene to the hydroxyl group of neolig- analysis (Fig. 1). In agreement with the results of a previous 718 Vol. 49, No. 6 2 Table 1. Inhibitory Effects of Constituents from the Bark of M. obovata on NO2 Accumulation in LPS-Activated Mouse Macrophages Inhibition (%) Compounds 3 10 30 100 IC50 (m M) Neolignans Magnolol (1) 1.462.9 9.261.9** 40.362.8** 100.861.0**,a) 34 Honokiol (2) 21.263.8 11.262.1* 73.263.3** 102.061.4**,a) 21 Obovatol (3) 21.867.6 1.1613.5 50.266.0** 80.964.4**,a) 28 4-O-Methylhonokiol (4) 8.162.2 2.566.5 9.862.7 56.568.6** 88 69-O-Methylhonokiol (5) 23.463.7 23.465.7 31.063.3 32.862.0 .100 Sesquiterpene-neolignans Eudesmagnolol (6) 216.361.8 212.164.0 28.464.8**,a) 98.361.1**,a) — Clovanemagnolol (7) 6.966.9 10.163.0 76.365.5**,a) 99.062.7**,a) — Caryolanemagnolol (8) 2.960.8 11.461.5a) 20.661.8**,a) 97.560.5**,a) — Eudeshonokiol A (9) 22.763.1 23.562.8 25.963.0**,a) 99.760.2**,a) — Eudeshonokiol B (10) 29.662.9 27.062.1 10.962.6** 97.360.4**,a) — Eudesobovatol A (11) 213.461.3 9.861.4 12.263.3a) 93.763.0**,a) — Eudesobovatol B (12) 21.265.0 12.666.3** 37.262.5** 89.261.9**,a) — Trineolignan Magnolianin (13) 212.962.4 29.262.3 28.664.1 212.962.6 .100 Phenylpropanoid glycoside Syringin (14) 22.462.6 21.663.3 23.462.0 9.463.1 .100 Lignan glycosides Liriodendrin (15) 20.164.6 25.263.7 23.864.6 23.563.6 .100 (1)-Syringaresinol 49-O-b-D-glucopyranoside (16) 7.662.9 4.464.1 9.862.7 13.566.6 .100 Sesquiterpene Caryophyllene oxide (17) 11.167.3 24.667.7 0.569.6 26.066.4** .100 6 5 ∗ , ∗∗ , Values represent means S.E.M.
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