Induction of central signalling pathways and select functional effects in human platelets by β ‐boswellic acid

We have recently shown that in polymorphonuclear leukocytes, 11‐keto boswellic acids (KBAs) induce Ca 2+ 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 β ‐BA (10  μ M ), the 11‐methylene analogue of KBA, caused a pronounced mobilisation of Ca 2+ from internal stores and induced the phosphorylation of p38 MAPK, extracellular signal‐regulated kinase (ERK)2, and Akt. These effects of β ‐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, β ‐BA triggers Ca 2+ mobilisation via the phospholipase (PL)C/inositol‐1,4,5‐trisphosphate pathway, and involves Src family kinase signalling. Investigation of platelet functions revealed that β ‐BA (10  μ M ) 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 Ca 2+ ‐dependent manner. In contrast to β ‐BA, the 11‐keto‐BAs (KBA or AKBA) evoke only moderate Ca 2+ 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, β ‐BA potently induces Ca 2+ mobilisation as well as the activation of pivotal protein kinases, and elicits functional platelet responses such as thrombin generation, liberation of AA, and aggregation.British Journal of Pharmacology (2005) 146 , 514–524. doi: 10.1038/sj.bjp.0706366