title: Induction of central signalling pathways and select functional effects in human platelets by beta-boswellic acid.
abstract: We have recently shown that in polymorphonuclear leukocytes, 11-keto boswellic acids (KBAs) induce Ca2+ mobilisation and activation of mitogen-activated protein kinases (MAPK). Here we addressed the effects of BAs on central signalling pathways in human platelets and on various platelet functions. We found that beta-BA (10 microM), the 11-methylene analogue of KBA, caused a pronounced mobilisation of Ca2+ from internal stores and induced the phosphorylation of p38 MAPK, extracellular signal-regulated kinase (ERK)2, and Akt. These effects of beta-BA were concentration dependent, and the magnitude of the responses was comparable to those obtained after platelet stimulation with thrombin or collagen. Based on inhibitor studies, beta-BA triggers Ca2+ mobilisation via the phospholipase (PL)C/inositol-1,4,5-trisphosphate pathway, and involves Src family kinase signalling. Investigation of platelet functions revealed that beta-BA (> or =10 microM) strongly stimulates the platelet-induced generation of thrombin in an ex-vivo in-vitro model, the liberation of arachidonic acid (AA), and induces platelet aggregation in a Ca2+-dependent manner. In contrast to beta-BA, the 11-keto-BAs (KBA or AKBA) evoke only moderate Ca2+ mobilisation and activate p38 MAPK, but fail to induce phosphorylation of ERK2 or Akt, and do not cause aggregation or significant generation of thrombin. In summary, beta-BA potently induces Ca2+ mobilisation as well as the activation of pivotal protein kinases, and elicits functional platelet responses such as thrombin generation, liberation of AA, and aggregation.
authors.affiliation: Institute of Pharmaceutical Chemistry, University of Frankfurt, Marie-Curie-Str. 9, Frankfurt D-60439, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Poeckel
authors.forename: Lars
authors.initials: L
authors.lastname: Tausch
authors.forename: Anja
authors.initials: A
authors.lastname: Altmann
authors.forename: Christian
authors.initials: C
authors.lastname: Feisst
authors.forename: Ute
authors.initials: U
authors.lastname: Klinkhardt
authors.forename: Jochen
authors.initials: J
authors.lastname: Graff
authors.forename: Sebastian
authors.initials: S
authors.lastname: Harder
authors.forename: Oliver
authors.initials: O
authors.lastname: Werz
mesh_terms: D000704:Analysis of Variance; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D020013:Calcium Signaling / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013917:Thrombin / Q000378:metabolism; D013997:Time Factors; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D014315:Triterpenes; D016718:Arachidonic Acid; C054625:boswellic acid; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D013917:Thrombin