title: Reversal of NO-induced nociceptive hypersensitivity by St. John's wort and hypericin: NF-κB, CREB and STAT1 as molecular targets.
abstract: BACKGROUND
  Hypericum perforatum, popularly called St. John's wort (SJW), is a medicinal plant mainly used as antidepressant with a favorable safety profile than standard antidepressants. Some studies have also documented other SJW bioactivities, including pain modulation.
  
  
  OBJECTIVE
  The aim of this study was to demonstrate the capability of SJW to relieve nitric oxide (NO)-induced nociceptive hypersensitivity and identify the effective component.
  
  
  METHODS
  Nociceptive hypersensitivity induced by administration of the NO donors nitroglycerin (GTN) and sodium nitroprusside (SNP) was assessed by cold and hot plate tests. The cellular pathways and molecular targets involved were investigated by Western blotting.
  
  
  RESULTS
  GTN and SNP produced a prolonged allodynia and hyperalgesia in mice. A single oral administration of low doses of an SJW dried extract or purified hypericin reversed the NO donor-induced nociceptive behavior whereas hyperforin and flavoinoids were ineffective. Investigating into the cellular pathways involved, an increased CREB and STAT1 phosphorylation, and activation of NF-κB were detected within PAG and thalamus following NO donors' administration. These cellular events were prevented by SJW or hypericin. Since hypericin showed PKC blocking properties, a role of PKC as an upstream modulator of these transcription factors was hypothesized. NO donors increased expression and phosphorylation of protein kinase C (PKC) γ and ε isoforms, molecular events prevented by SJW or hypericin.
  
  
  CONCLUSIONS
  SJW reversed NO-induced nociceptive hypersensitivity through the blockade of a supraspinal signaling pathway involving a PKC-dependent CREB, STAT1 and NF-κB activation due to presence of hypericin. These data indicate SJW/hypericin as a therapeutic perspective for pain treatment.
authors.affiliation: Department of Preclinical and Clinical Pharmacology, Viale G. Pieraccini 6, 50139, Florence, Italy. nicoletta.galeotti@unifi.it
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Galeotti
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
mesh_terms: D000818:Animals; D000873:Anthracenes; D050882:CREB-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003080:Cold Temperature / Q000009:adverse effects; D006358:Hot Temperature / Q000009:adverse effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D020902:Hypericum; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000633:toxicity*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010569:Perylene / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D010936:Plant Extracts / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011897:Random Allocation; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000873:Anthracenes; D016328:NF-kappa B; D020030:Nitric Oxide Donors; D010936:Plant Extracts; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D009569:Nitric Oxide; D010569:Perylene; C004965:hypericin; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D011493:Protein Kinase C