The mechanisms and actions of parthenolide on platelet 5-HT secretion in vitro: indicating a possible pathogenesis of the migraine

Extracts of the medicinal herb feverfew and its active compound, parthenolide, have been determined to have anti-inflammatory, anti-migraine, and anti-cancerous effects, though the biochemical pathways involved have not been fully characterized. Both inhibit human platelet aggregation and serotonin (5-HT) secretion and are hypothesized to inhibit the protein kinase C (PKC) pathway. PKC mediates the phosphorylation of the 5-HT transporter in platelets and induces 5-HT secretion when activated. A platelet-based model was used to mimic the behavior of 5-HT neurons, and PKC activation was measured by the amount of 5-HT secreted. 5-HT secretion was measured using a comparison between 5-HT concentrations in platelet-rich plasma (PRP) and platelet-poor plasma (PPP): if PKC was inactivated and the treated platelets retained 5HT, then PRP had a greater amount of 5-HT then PPP, if PKC was activated and 5-HT was secreted, then PRP and PPP had similar 5-HT concentrations. This study, using this model, indicates that platelets retain 5-HT when unclotted and release 5-HT when aggregated, thereby verifying the model appropriate for measuring platelet 5-HT secretion. This model also indicates that phorbol myristate acetate (PMA) induces platelet 5-HT secretion. Because aggregation of platelets and treatment with PMA have been correlated very strongly to PKC activation, this model is shown to be an accurate in-vitro model of PKC activation. This model suggests that parthenolide inhibits the PKC pathway, preventing 5-HT secretion; therefore the PKC pathway may be overactive in inflammatory diseases, certain cancers, and migraines, and drugs treating these diseases should target the PKC pathway.