Abstract
The protein kinase, p38α MAPK, is a key intracellular transducer of stressor-induced neuroinflammatory responses and, as such, is of high interest as a potential therapeutic target. We recently reported the synthesis and evaluation of first-in-class CNS-penetrant and highly specific p38 MAPK inhibitors that avoid target crossover issues seen in popular small molecule p38 MAPK inhibitors used in hundreds of previous reports. The novel p38 MAPK inhibitors, represented in this study by MW181, are efficacious in vivo. Pharmacodynamic actions include attenuation of stressor-induced increases in brain proinflammatory cytokine levels. We report here more detailed analyses of MW181 target engagement and specific linkage to the downstream increase in glia proinflammatory cytokine production. In vivo validation included demonstration that oral administration of MW181 suppresses lipopolysaccharide-induced increases in mouse brain IL-1β, TNFα, IL-6, IL-10, and CXCL1 but not in a drug-resistant p38α MAPK mutant mouse.
Original language | English (US) |
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Pages (from-to) | 454-460 |
Number of pages | 7 |
Journal | Journal of Neuroimmune Pharmacology |
Volume | 9 |
Issue number | 4 |
DOIs | |
State | Published - Sep 2014 |
Funding
Acknowledgments We thank Danielle Goulding for excellent technical assistance. This research was supported in part by funding from the Alzheimer’s Drug Discovery Foundation (DMW), and NIH grants R01 AG031311 (DMW), U01 AG043415 (DMW), and R01 NS064247 (LVE). ADB was supported in part by NIH/NIA (F32 AG037280 and K99AG044445).
Keywords
- Cytokine
- Drug discovery
- Microglia
- Mitogen-activated protein kinase
- Neurodegeneration
- Signal transduction
ASJC Scopus subject areas
- Neuroscience (miscellaneous)
- Immunology and Allergy
- Immunology
- Pharmacology