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Hyperforin, an Anti-Inflammatory Constituent from St. John's Wort, Inhibits Microsomal Prostaglandin E(2) Synthase-1 and Suppresses Prostaglandin E(2) Formation in vivo.

Koeberle A, Rossi A, Bauer J, Dehm F, Verotta L, Northoff H, Sautebin L, Werz O - Front Pharmacol (2011)

Bottom Line: The acylphloroglucinol hyperforin (Hyp) from St. John's wort possesses anti-inflammatory and anti-carcinogenic properties which were ascribed among others to the inhibition of 5-lipoxygenase.Intraperitoneal (i.p.) administration of Hyp (4 mg kg(-1)) to rats impaired exudate volume and leukocyte numbers in carrageenan-induced pleurisy associated with reduced PGE(2) levels, and Hyp (given i.p.) inhibited carrageenan-induced mouse paw edema formation (ED(50) = 1 mg kg(-1)) being superior over indomethacin (ED(50) = 5 mg kg(-1)).We conclude that the suppression of PGE(2) biosynthesis in vitro and in vivo by acting on mPGES-1 critically contributes to the anti-inflammatory efficiency of Hyp.

View Article: PubMed Central - PubMed

Affiliation: Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tübingen Tübingen, Germany.

ABSTRACT
The acylphloroglucinol hyperforin (Hyp) from St. John's wort possesses anti-inflammatory and anti-carcinogenic properties which were ascribed among others to the inhibition of 5-lipoxygenase. Here, we investigated whether Hyp also interferes with prostanoid generation in biological systems, particularly with key enzymes participating in prostaglandin (PG)E(2) biosynthesis, i.e., cyclooxygenases (COX)-1/2 and microsomal PGE(2) synthase (mPGES)-1 which play key roles in inflammation and tumorigenesis. Similar to the mPGES-1 inhibitors MK-886 and MD-52, Hyp significantly suppressed PGE(2) formation in whole blood assays starting at 0.03-1 μM, whereas the concomitant generation of COX-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid, thromboxane B(2), and 6-keto PGF(1α) was not significantly suppressed up to 30 μM. In cell-free assays, Hyp efficiently blocked the conversion of PGH(2) to PGE(2) mediated by mPGES-1 (IC(50) = 1 μM), and isolated COX enzymes were not (COX-2) or hardly (COX-1) suppressed. Intraperitoneal (i.p.) administration of Hyp (4 mg kg(-1)) to rats impaired exudate volume and leukocyte numbers in carrageenan-induced pleurisy associated with reduced PGE(2) levels, and Hyp (given i.p.) inhibited carrageenan-induced mouse paw edema formation (ED(50) = 1 mg kg(-1)) being superior over indomethacin (ED(50) = 5 mg kg(-1)). We conclude that the suppression of PGE(2) biosynthesis in vitro and in vivo by acting on mPGES-1 critically contributes to the anti-inflammatory efficiency of Hyp.

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Effects of hyperforin on carrageenan-induced mouse paw edema. (A) Animals (n = 10 for each experimental group) were treated i.p. with 0.25, 1, and 4 mg kg−1 Hyp, 5 mg kg−1 indomethacin, or vehicle (2% DMSO) 30 min before carrageenan subplantar injection. (B) Inhibition of edema formation caused by the treatment with the indicated compounds as percentage of vehicle control calculated from the relative areas under the curves. Data are given as mean ± SE. n = 10, *p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle (2% DMSO) control, ANOVA + Tukey HSD post hoc tests.
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Figure 6: Effects of hyperforin on carrageenan-induced mouse paw edema. (A) Animals (n = 10 for each experimental group) were treated i.p. with 0.25, 1, and 4 mg kg−1 Hyp, 5 mg kg−1 indomethacin, or vehicle (2% DMSO) 30 min before carrageenan subplantar injection. (B) Inhibition of edema formation caused by the treatment with the indicated compounds as percentage of vehicle control calculated from the relative areas under the curves. Data are given as mean ± SE. n = 10, *p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle (2% DMSO) control, ANOVA + Tukey HSD post hoc tests.

Mentions: The anti-inflammatory properties of Hyp were investigated in carrageenan-induced mouse paw edema in which PGE2 (and also other mediators) critically contributes to the inflammatory response (Guay et al., 2004). Hyp (0.25, 1, 4 mg kg−1) was administered i.p. 30 min prior to injection of carrageenan into the mouse paw. The increase in paw volume was time-dependently assessed and reached a maximum at 4-h post-carrageenan treatment (Figure 6A). In fact, in mice treated with 0.25, 1, and 4 mg kg−1 of Hyp, the peak of the response to carrageenan at 4 h was reduced by 35, 63, and 78%, respectively, whereas indomethacin (5 mg kg−1), used as reference, caused 57% inhibition. Moreover, comparison of the areas under the curves of each group, between 2 and 6 h after carrageenan injection, yielded similar degrees of inhibition confirming a more potent effect of Hyp (ED50 = 1 mg kg−1) over indomethacin (ED50 = 5 mg kg−1; Figure 6B).


Hyperforin, an Anti-Inflammatory Constituent from St. John's Wort, Inhibits Microsomal Prostaglandin E(2) Synthase-1 and Suppresses Prostaglandin E(2) Formation in vivo.

Koeberle A, Rossi A, Bauer J, Dehm F, Verotta L, Northoff H, Sautebin L, Werz O - Front Pharmacol (2011)

Effects of hyperforin on carrageenan-induced mouse paw edema. (A) Animals (n = 10 for each experimental group) were treated i.p. with 0.25, 1, and 4 mg kg−1 Hyp, 5 mg kg−1 indomethacin, or vehicle (2% DMSO) 30 min before carrageenan subplantar injection. (B) Inhibition of edema formation caused by the treatment with the indicated compounds as percentage of vehicle control calculated from the relative areas under the curves. Data are given as mean ± SE. n = 10, *p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle (2% DMSO) control, ANOVA + Tukey HSD post hoc tests.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 6: Effects of hyperforin on carrageenan-induced mouse paw edema. (A) Animals (n = 10 for each experimental group) were treated i.p. with 0.25, 1, and 4 mg kg−1 Hyp, 5 mg kg−1 indomethacin, or vehicle (2% DMSO) 30 min before carrageenan subplantar injection. (B) Inhibition of edema formation caused by the treatment with the indicated compounds as percentage of vehicle control calculated from the relative areas under the curves. Data are given as mean ± SE. n = 10, *p < 0.05, **p < 0.01, ***p < 0.001 vs. vehicle (2% DMSO) control, ANOVA + Tukey HSD post hoc tests.
Mentions: The anti-inflammatory properties of Hyp were investigated in carrageenan-induced mouse paw edema in which PGE2 (and also other mediators) critically contributes to the inflammatory response (Guay et al., 2004). Hyp (0.25, 1, 4 mg kg−1) was administered i.p. 30 min prior to injection of carrageenan into the mouse paw. The increase in paw volume was time-dependently assessed and reached a maximum at 4-h post-carrageenan treatment (Figure 6A). In fact, in mice treated with 0.25, 1, and 4 mg kg−1 of Hyp, the peak of the response to carrageenan at 4 h was reduced by 35, 63, and 78%, respectively, whereas indomethacin (5 mg kg−1), used as reference, caused 57% inhibition. Moreover, comparison of the areas under the curves of each group, between 2 and 6 h after carrageenan injection, yielded similar degrees of inhibition confirming a more potent effect of Hyp (ED50 = 1 mg kg−1) over indomethacin (ED50 = 5 mg kg−1; Figure 6B).

Bottom Line: The acylphloroglucinol hyperforin (Hyp) from St. John's wort possesses anti-inflammatory and anti-carcinogenic properties which were ascribed among others to the inhibition of 5-lipoxygenase.Intraperitoneal (i.p.) administration of Hyp (4 mg kg(-1)) to rats impaired exudate volume and leukocyte numbers in carrageenan-induced pleurisy associated with reduced PGE(2) levels, and Hyp (given i.p.) inhibited carrageenan-induced mouse paw edema formation (ED(50) = 1 mg kg(-1)) being superior over indomethacin (ED(50) = 5 mg kg(-1)).We conclude that the suppression of PGE(2) biosynthesis in vitro and in vivo by acting on mPGES-1 critically contributes to the anti-inflammatory efficiency of Hyp.

View Article: PubMed Central - PubMed

Affiliation: Department for Pharmaceutical Analytics, Pharmaceutical Institute, University of Tübingen Tübingen, Germany.

ABSTRACT
The acylphloroglucinol hyperforin (Hyp) from St. John's wort possesses anti-inflammatory and anti-carcinogenic properties which were ascribed among others to the inhibition of 5-lipoxygenase. Here, we investigated whether Hyp also interferes with prostanoid generation in biological systems, particularly with key enzymes participating in prostaglandin (PG)E(2) biosynthesis, i.e., cyclooxygenases (COX)-1/2 and microsomal PGE(2) synthase (mPGES)-1 which play key roles in inflammation and tumorigenesis. Similar to the mPGES-1 inhibitors MK-886 and MD-52, Hyp significantly suppressed PGE(2) formation in whole blood assays starting at 0.03-1 μM, whereas the concomitant generation of COX-derived 12(S)-hydroxy-5-cis-8,10-trans-heptadecatrienoic acid, thromboxane B(2), and 6-keto PGF(1α) was not significantly suppressed up to 30 μM. In cell-free assays, Hyp efficiently blocked the conversion of PGH(2) to PGE(2) mediated by mPGES-1 (IC(50) = 1 μM), and isolated COX enzymes were not (COX-2) or hardly (COX-1) suppressed. Intraperitoneal (i.p.) administration of Hyp (4 mg kg(-1)) to rats impaired exudate volume and leukocyte numbers in carrageenan-induced pleurisy associated with reduced PGE(2) levels, and Hyp (given i.p.) inhibited carrageenan-induced mouse paw edema formation (ED(50) = 1 mg kg(-1)) being superior over indomethacin (ED(50) = 5 mg kg(-1)). We conclude that the suppression of PGE(2) biosynthesis in vitro and in vivo by acting on mPGES-1 critically contributes to the anti-inflammatory efficiency of Hyp.

No MeSH data available.


Related in: MedlinePlus