Development of Novel In Vivo Chemical Probes to Address CNS Protein Kinase Involvement in Synaptic Dysfunction
Figure 7
Cellular target engagement and mechanism of action of MW181.
A. MW181 inhibited phosphorylation of the p38αMAPK substrate MK2 in a concentration-dependent manner in LPS-stimulated BV-2 microglial cells. B. MW181 inhibited LPS-induced IL-1β production in a concentration-dependent manner in BV-2 cells. C. MW-181 suppressed IL-1β production in BV-2 cells stimulated with diverse TLR ligands. BV-2 cells were treated with ligands for TLR2, TLR4, TLR7/8, and TLR9 in the absence (white bars) or presence (gray bars) of MW181. ‡ p<0.0001 compared to TLR ligand in the absence of compound. D. MW181 inhibited LPS-induced IL-1β production in primary microglia from wild-type (WT) mice, but not from drug-resistant p38αMAPK knock-in (p38α KI) mice. # p<0.01, § p<0.001 compared to LPS alone. E. MW181 suppressed LPS-induced IL-1β levels in vivo. **p<0.01 compared to LPS alone (n = 6 saline/vehicle; n = 24 LPS/vehicle; n = 15 LPS/MW181). Data in all panels are expressed as a percent of the maximal levels, where levels in the presence of stressor alone were normalized to 100%.