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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.

No MeSH data available.


Related in: MedlinePlus

Effects of hyperforin on prostanoid formation in LPS-stimulated human whole blood. (A) Chemical structure of Hyp. (B,C) Heparinized human whole blood, treated with 1 μM TX synthase inhibitor CV4151 and 50 μM aspirin, was pre-incubated with the indicated agents or vehicle (DMSO) for 5 min at room temperature, and then, prostanoid formation was induced by addition of 10 μg ml−1 LPS. After 5 h at 37°C, PGE2 (B) was extracted from plasma by RP-18 solid phase extraction, separated by RP-HPLC, and quantified by ELISA as described. 6-Keto PGF1α (C) and TXB2 (D) were directly determined in the plasma by ELISA. The 100% values correspond to prostanoid levels in the range of 14–27 ng ml−1 PGE2, 3–5 ng ml−1 6-keto PGF1α, and 47–64 ng ml−1 TXB2 in the individual experiments, respectively. MK-886 (30 μM), MD-52 (6 μM), indomethacin (Indo, 50 μM), and celecoxib (Cele, 20 μM) were used as controls. Data are given as mean ± SE, n = 3–4, *p < 0.05, ***p < 0.001 vs. vehicle (0.1% DMSO) control, ANOVA + Tukey HSD post hoc tests.
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Figure 1: Effects of hyperforin on prostanoid formation in LPS-stimulated human whole blood. (A) Chemical structure of Hyp. (B,C) Heparinized human whole blood, treated with 1 μM TX synthase inhibitor CV4151 and 50 μM aspirin, was pre-incubated with the indicated agents or vehicle (DMSO) for 5 min at room temperature, and then, prostanoid formation was induced by addition of 10 μg ml−1 LPS. After 5 h at 37°C, PGE2 (B) was extracted from plasma by RP-18 solid phase extraction, separated by RP-HPLC, and quantified by ELISA as described. 6-Keto PGF1α (C) and TXB2 (D) were directly determined in the plasma by ELISA. The 100% values correspond to prostanoid levels in the range of 14–27 ng ml−1 PGE2, 3–5 ng ml−1 6-keto PGF1α, and 47–64 ng ml−1 TXB2 in the individual experiments, respectively. MK-886 (30 μM), MD-52 (6 μM), indomethacin (Indo, 50 μM), and celecoxib (Cele, 20 μM) were used as controls. Data are given as mean ± SE, n = 3–4, *p < 0.05, ***p < 0.001 vs. vehicle (0.1% DMSO) control, ANOVA + Tukey HSD post hoc tests.

Mentions: Hyperforin (Hyp), a polyprenylated acylphloroglucinol (Figure 1A), is assumed to be one of the main active components of St. John's wort, which is frequently used for the treatment of mild to moderate depressions (Muller, 2003). Besides its antidepressant activity, Hyp also exerts potent anti-inflammatory and anti-tumoral effects (Medina et al., 2006). Hyp was shown to reduce tumor cell growth (Schempp et al., 2002; Hostanska et al., 2003), cancer invasion, metastasis (Dona et al., 2004), angiogenesis (Martinez-Poveda et al., 2005), and lymphatic capillary growth (Rothley et al., 2009). On the cellular level, Hyp decreases proliferation rates and causes apoptosis of leukemic cells (Schempp et al., 2002; Quiney et al., 2006) and various cancer cell lines (Schempp et al., 2002; Hostanska et al., 2003; Dona et al., 2004), and also inhibits proliferation of non-transformed T lymphocytes (Schempp et al., 2000). In regard of its anti-inflammatory potential, Hyp blocks several pro-inflammatory functions of leukocytes in vitro such as chemotaxis and chemoinvasion (Dell'Aica et al., 2007; Lorusso et al., 2009), suppresses receptor-mediated Ca2+-mobilization and eicosanoid release in leukocytes (Albert et al., 2002; Feisst and Werz, 2004), and down-regulates effector functions of activated T lymphocytes (Cabrelle et al., 2008). In vivo, Hyp reduced croton-oil-induced ear edema in mice after topical application (Sosa et al., 2007), impaired acute neutrophil recruitment and enhanced resolution in a pulmonary bleomycin-induced inflammation model reducing consequent fibrosis (Dell'Aica et al., 2007), and suppressed carrageenan-induced rat pleurisy when given intraperitoneally (i.p.; Feisst et al., 2009). Also for humans, topical treatment of atopic dermatitis with a Hypericum cream, standardized to 1.5% Hyp, revealed significant therapeutic efficacy (Schempp et al., 2003). However, despite these well-recognized anti-carcinogenic and anti-inflammatory effects, the underlying molecular mechanisms and targets of Hyp are incompletely understood.


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 prostanoid formation in LPS-stimulated human whole blood. (A) Chemical structure of Hyp. (B,C) Heparinized human whole blood, treated with 1 μM TX synthase inhibitor CV4151 and 50 μM aspirin, was pre-incubated with the indicated agents or vehicle (DMSO) for 5 min at room temperature, and then, prostanoid formation was induced by addition of 10 μg ml−1 LPS. After 5 h at 37°C, PGE2 (B) was extracted from plasma by RP-18 solid phase extraction, separated by RP-HPLC, and quantified by ELISA as described. 6-Keto PGF1α (C) and TXB2 (D) were directly determined in the plasma by ELISA. The 100% values correspond to prostanoid levels in the range of 14–27 ng ml−1 PGE2, 3–5 ng ml−1 6-keto PGF1α, and 47–64 ng ml−1 TXB2 in the individual experiments, respectively. MK-886 (30 μM), MD-52 (6 μM), indomethacin (Indo, 50 μM), and celecoxib (Cele, 20 μM) were used as controls. Data are given as mean ± SE, n = 3–4, *p < 0.05, ***p < 0.001 vs. vehicle (0.1% DMSO) control, ANOVA + Tukey HSD post hoc tests.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108608&req=5

Figure 1: Effects of hyperforin on prostanoid formation in LPS-stimulated human whole blood. (A) Chemical structure of Hyp. (B,C) Heparinized human whole blood, treated with 1 μM TX synthase inhibitor CV4151 and 50 μM aspirin, was pre-incubated with the indicated agents or vehicle (DMSO) for 5 min at room temperature, and then, prostanoid formation was induced by addition of 10 μg ml−1 LPS. After 5 h at 37°C, PGE2 (B) was extracted from plasma by RP-18 solid phase extraction, separated by RP-HPLC, and quantified by ELISA as described. 6-Keto PGF1α (C) and TXB2 (D) were directly determined in the plasma by ELISA. The 100% values correspond to prostanoid levels in the range of 14–27 ng ml−1 PGE2, 3–5 ng ml−1 6-keto PGF1α, and 47–64 ng ml−1 TXB2 in the individual experiments, respectively. MK-886 (30 μM), MD-52 (6 μM), indomethacin (Indo, 50 μM), and celecoxib (Cele, 20 μM) were used as controls. Data are given as mean ± SE, n = 3–4, *p < 0.05, ***p < 0.001 vs. vehicle (0.1% DMSO) control, ANOVA + Tukey HSD post hoc tests.
Mentions: Hyperforin (Hyp), a polyprenylated acylphloroglucinol (Figure 1A), is assumed to be one of the main active components of St. John's wort, which is frequently used for the treatment of mild to moderate depressions (Muller, 2003). Besides its antidepressant activity, Hyp also exerts potent anti-inflammatory and anti-tumoral effects (Medina et al., 2006). Hyp was shown to reduce tumor cell growth (Schempp et al., 2002; Hostanska et al., 2003), cancer invasion, metastasis (Dona et al., 2004), angiogenesis (Martinez-Poveda et al., 2005), and lymphatic capillary growth (Rothley et al., 2009). On the cellular level, Hyp decreases proliferation rates and causes apoptosis of leukemic cells (Schempp et al., 2002; Quiney et al., 2006) and various cancer cell lines (Schempp et al., 2002; Hostanska et al., 2003; Dona et al., 2004), and also inhibits proliferation of non-transformed T lymphocytes (Schempp et al., 2000). In regard of its anti-inflammatory potential, Hyp blocks several pro-inflammatory functions of leukocytes in vitro such as chemotaxis and chemoinvasion (Dell'Aica et al., 2007; Lorusso et al., 2009), suppresses receptor-mediated Ca2+-mobilization and eicosanoid release in leukocytes (Albert et al., 2002; Feisst and Werz, 2004), and down-regulates effector functions of activated T lymphocytes (Cabrelle et al., 2008). In vivo, Hyp reduced croton-oil-induced ear edema in mice after topical application (Sosa et al., 2007), impaired acute neutrophil recruitment and enhanced resolution in a pulmonary bleomycin-induced inflammation model reducing consequent fibrosis (Dell'Aica et al., 2007), and suppressed carrageenan-induced rat pleurisy when given intraperitoneally (i.p.; Feisst et al., 2009). Also for humans, topical treatment of atopic dermatitis with a Hypericum cream, standardized to 1.5% Hyp, revealed significant therapeutic efficacy (Schempp et al., 2003). However, despite these well-recognized anti-carcinogenic and anti-inflammatory effects, the underlying molecular mechanisms and targets of Hyp are incompletely understood.

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