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.
Highlights
Neuroinflammation is a complex process that can be profoundly influenced by the cellular and environmental context, disease stage, and inciting stimuli
The studies reported here demonstrate that MW181 engages the p38α MAPK target in its glia cellular context and links the target engagement to the downstream pharmacodynamic effect of normalized CNS proinflammatory cytokine levels
The in vivo selectivity of MW181 action is further indicated by the failure to bring about its pharmacodynamic effects in p38α MAPK inhibitor resistant mice
Summary
Neuroinflammation is a complex process that can be profoundly influenced by the cellular and environmental context, disease stage, and inciting stimuli. As the resident tissue macrophage, are the archetypal cell in the CNS neuroinflammatory response. Astrocytes, along with microglia, represent the resident cells in the nervous system responsible for neuroinflammation. Infection, or other disturbances, microglia and astrocytes activate a patterned response to defend against and isolate inducing stimuli, which is followed by healing, repair, and resolution of the neuroinflammation. The reactive response of glia is fundamental for CNS homeostasis. The reactive glia response is context specific and highly variable, which can cause beneficial and/or detrimental forms of neuroinflammation (for a review of reactive gliosis see: Burda and Sofroniew 2014)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
