Hyperforin Blocks Neutrophil Activation of Matrix Metalloproteinase-9, Motility and Recruitment, and Restrains Inflammation-Triggered Angiogenesis and Lung Fibrosis

Abstract

Hyperforin (Hyp), a polyphenol-derivative of St. John's wort (Hypericum perforatum), has emerged as key player not only in the antidepressant activity of the plant but also as an inhibitor of bacteria lymphocyte and tumor cell proliferation, and matrix proteinases. We tested whether as well as inhibiting leukocyte elastase (LE) activity, Hyp might be effective in containing both polymorphonuclear neutrophil (PMN) leukocyte recruitment and unfavorable eventual tissue responses. The results show that, without affecting in vitro human PMN viability and chemokine-receptor expression, Hyp (as stable dicyclohexylammonium salt) was able to inhibit in a dose-dependent manner their chemotaxis and chemoinvasion (IC 50 ϭ 1 M for both); this effect was associated with a reduced expression of the adhesion molecule CD11b by formyl-Met-Leu-Phe-stimulated neutrophils and block of LE-triggered activation of the gelatinase matrix metalloproteinase-9. PMN-triggered angiogenesis is also blocked by both local injection and daily i.p. administration of the Hyp salt in an interleukin-8-induced murine model. Furthermore, i.p. treatment with Hyp reduces acute PMN recruitment and enhances resolution in a pulmonary bleomycin-induced inflammation model, significantly reducing consequent fibrosis. These results indicate that Hyp is a powerful antiinflammatory compound with therapeutic potential, and they elucidate mechanistic keys.

Hyperforin is a novel type of 5-lipoxygenase inhibitor with high efficacy in vivo

“…The effectiveness of hyperforin as a novel inhibitor of LT synthesis is strengthened by its in vivo action as demonstrated by the reduced LTB 4 generation in rat pleural exudates associated with an anti-inflammatory action, comparable to zileuton. Along these lines, hyperforin was previously demonstrated to reduce acute neutrophil recruitment and to enhance resolution in a murine pulmonary bleomycin-induced inflammation model, significantly reducing consequent fibrosis [38]. Targeting of the functionality of the C2-like domain of 5-LO may represent a novel pharmacological approach for future 5-LO inhibitor developments.…”

St. John’s wort and its component hyperforin alleviate experimental autoimmune encephalomyelitis through expansion of regulatory T-cells

“…Studies have indicated that HP contains bioactive constituents, including hyperforin (phloroglucinol), hypericin (naphthodianthrone), flavonoids and tannins (Barnes et al 2001). Pharmacological studies have shown that hyperforin is the major component responsible for the anti-depressant and anti-inflammatory activities associated with the use of HP (Bhattacharya et al 1998;Dell'Aica et al 2007;Meinke et al 2012).…”

Modulation of Inflammation by Cicaderma Ointment Accelerates Skin Wound Healing

“…In addition, the activation of the fibroblasts and their increased collagen production by H. perforatum L. (Oztü rk et al, 2007) strengthen the beneficial effects of Cicaderma in the granulation phase of wound healing. H. perforatum L. was also described to reduce in vivo the recruitment of PMNs attaching to the vascular endothelium at the site of injury, leading to a diminution of inflammation and angiogenesis (Dell'Aica et al, 2007b). This can be linked to the decrease of PMNs, considered as inflammatory markers, in the wound bed of Cicaderma-treated ulcers.…”