Despite the great number of approved anti-inflammatory drugs, the treatment of chronic inflammatory diseases, such as multiple sclerosis or rheumatoid arthritis, is still a therapeutical challenge. Thus, there is an ongoing need for new anti-inflammatory lead compounds. In this context, narciclasine, an Amaryllidaceae alkaloid, was found to exert anti-inflammatory properties.1 The goal of our project is the preclinical characterization of narciclasine as an anti-inflammatory agent, in particular, the identification of its mode of action. In vivo, narciclasine inhibited the rolling, firm adhesion and transmigration of leukocytes into the TNFα-activated cremaster muscle of C57BL/6 mice (intravital microscopy). In vitro, narciclasine significantly reduced the TNFα-triggered adhesion of T cells (Jurkat), monocytic cells (THP-1) and primary mononuclear cells to primary endothelial cells. As adhesion was reduced, we investigated the influence of narciclasine on the expression of endothelial cell adhesion molecules and chemokines. Narciclasine significantly downregulated endothelial ICAM-1 (IC50: 54 nM), VCAM-1 (IC50: 30 nM), E-selectin (IC50: 51 nM) and CX3CL1 protein expression (flow cytometry, western blot analysis). Interestingly, narciclasine did neither influence the activation of the mitogen-activated protein kinases p38 and JNK, nor the NF-κB activation pathway (IκBα expression, p65 translocation). However, narciclasine strongly inhibited the NF-κB-dependent gene expression (reporter gene assay), indicating a transcriptional or translational mechanism. Taken together, the anti-inflammatory property of narciclasine could be based on the inhibition of leukocyte-endothelial cell interaction. This action is due to a downregulation of the expression of endothelial cell adhesion molecules and chemokines. The precise molecular mechanism of action of narciclasine will be the subject of our further investigations.
[1] Fuchs S, Hsieh LT, Saarberg W, Erdelmeier CA, Wichelhaus TA, Schaefer L, Koch E, Fürst R. J Cell Mol Med 2015; 19: 1021 – 1032
