Figure 9

Proposed mechanism of LPS signaling in microglia leading to endothelial, and microglial cell death. LPS binds toll-like receptor 4 (TLR4) on the surface of microglia leading to signaling in several pathways., NF-κB, the MAPKs and JAK-STAT. MAPKs then activate JNK (JNK kinase) and the p38 MAPK (p38). NF-κB, JAK-STAT and to a lesser extent, JNK lead to upregulation of immune factors iNOS and NADPH oxidase (NOX). These factors lead to the production of nitric oxide (NO) and superoxide (O2-), respectively. These molecules are themselves known to be directly cytoxic, but may also combine to form peroxynitrite (ONOO-) which can also kill cells. Also indicated in the figure are the NF-κB, p38 MAPK, JAK-STAT and JNK inhibitors studied. (PDTC = pyrrolidinecarbodithoic acid).