Reversal of NO-induced nociceptive hypersensitivity by St. John’s wort and hypericin: NF-κB, CREB and STAT1 as molecular targets

Abstract

Rationale 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. Objectives 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.

Quercetin ameliorates paclitaxel-induced neuropathic pain by stabilizing mast cells, and subsequently blocking PKCε-dependent activation of TRPV1

“…The excessive expression of TRPV1 was strongly inhibited by quercetin, which indicates that quercetin might relieve paclitaxel-produced thermal hyperalgesia through the down-modulation of TRPV1 and PKCε. The PKC blocker hypericin has been proven to attenuate NO-induced nociceptive hypersensitivity, and this decrease is accompanied by a decreased expression of PKCε [48] . In a mouse model of paclitaxel-induced neuropathy, increased mast cell tryptase activity in the spinal cord, DRGs and peripheral tissues have been observed to be correlated with the repetitive administration of paclitaxel.…”

Effect of the extract of Hypericum perforatum on neurodevelopment of regions related to pain control and convulsion

“…Thus, it decreases the expression of transcription factors including Signal Transducer and Activator of Transcription (STAT-1), NFand Cyclic AMP response element binding protein (CREB), involved in the activation of intracellular pathways in the APG and thalamus of mice (Galeotti et al, 2010b;Galeotti and Ghelardini, 2013). These mechanisms explain the synergistic interaction of hyperforin and hypericin present in the EHP to promote the antinociceptive response which is lasting and maintained into the adulthood of rats analyzed in this study.…”

Neuronal effects of a nickel-piperazine/NO donor complex in rodents

“…Indeed, iNOS upregulation and PKC translocation and activation in response to NO donors have been reported ( [22,23,2]). SHR rats showed higher basal levels of iNOS and PKC proteins were than WKY.…”

“…Peripheral administration of NO donors in laboratory animals produced pain hypersensitivity 2-4 h after injection [22,23]. The effect produced by Ni(PipNONO)Cl on the pain threshold following an acute mechanical stimulus was, then, evaluated in mice and rats.…”