Tolbutamide is a first generation potassium channel blocker

by Selleckchem | Feb 01 2013

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by excessive and chronic activation of inflammatory pathways via immune Tolbutamide complex deposition, complement activation, and Fc receptor (FcR) ligation, often leading to significant clinical pathologies including glomerulonephritis, immune thrombocytopenic purpura, hemolytic anemia, polyserositis, and vasculitis in humans. Mapping studies have revealed a region on telomeric chromosome 1 in mice and the syntenic region in humans that often show strong linkage to lupus. Observations in nonautoimmune mice carrying chromosome 1 regions from lupus-prone strains have further elucidated that genes in this region encoding Fc_RII (CD32) and Fc_RIII (CD16) are important risk factors for disease.

FcR_-deficient (NZB _ NZW)F1 (NZB/NZW) mice generate and deposit immune complex and activate complement but are protected from severe nephritis, suggesting that the downstream inflammatory events are dependent on FcR_ expression. U0126 FcR_ deficiency reduces experimental hemolytic anemia and thrombocytopenia in mice and modulates development of anti?Cglomerular basement membrane (anti-GBM) antibody?Cinduced Triciribine glomerulonephritis. Studies using bone marrow chimera strategies to produce mice with FcR_ deficiency in specific cell compartments have shown that hematopoietic cell expression of FcR, and not kidney mesangial cell expression, is required for spontaneous disease development in lupus-prone NZB/ NZW mice as well as for development of anti-GBM?C induced nephritis, suggesting that inhibition of FcR signaling in circulating leukocytes would potentially be sufficient to ameliorate tissue-specific inflammation.
NZB/NZW mice given soluble Fc_RIII demonstrate Valproic acid reduced anti?Cdouble-stranded DNA (antidsDNA) antibody levels, decreased proteinuria, and prolonged survival, providing significant rationale for targeting FcR pathways for the treatment of lupus. B cells also play a significant role in lupus pathogenesis via production of autoantibodies, resulting in antigen?Cantibody immune complex formation and stimulation of FcR. B cell receptors and FcR share a common signaling pathway, and both are transmembrane molecules containing immunoreceptor tyrosine?C based activation motif (ITAM) or immunoreceptor tyrosine?Cbased inhibition motif (ITIM), depending on Varespladib the receptor type, which become phosphorylated by Src family kinases.
The dual phosphorylation of ITAMs provides for high-affinity interaction with spleen tyrosine kinase (Syk), a molecule that is crucial for the signaling of B cell receptors and activating FcR. Because the pathogenesis of SLE has been associated with FcR expression and autoreactive B cells, we hypothesized that inhibition of Syk using a recently described orally bioavailable small molecule Syk-selective inhibitor (R406), prepared as a prodrug (R788), would ameliorate disease in spontaneous lupus Cprone mice.