Characterization of Novel Src Family Kinase Inhibitors to Attenuate Microgliosis
View/ Open
Author
Manocha, Gunjan D.
Puig, Kendra L.
Austin, Susan A.
Seyb, Kathleen
Combs, Colin K.
Published Version
https://doi.org/10.1371/journal.pone.0132604Metadata
Show full item recordCitation
Manocha, Gunjan D., Kendra L. Puig, Susan A. Austin, Kathleen Seyb, Marcie A. Glicksman, and Colin K. Combs. 2015. “Characterization of Novel Src Family Kinase Inhibitors to Attenuate Microgliosis.” PLoS ONE 10 (7): e0132604. doi:10.1371/journal.pone.0132604. http://dx.doi.org/10.1371/journal.pone.0132604.Abstract
Microgliosis is a major hallmark of Alzheimer’s disease (AD) brain pathology. Aβ peptide is hypothesized to act as a stimulus for microglia leading to activation of non-receptor tyrosine kinases and subsequent secretion of pro-inflammatory cytokines. Therefore, the signaling pathways mediating microglial activation may be important therapeutic targets of anti-inflammatory therapy for AD. Four novel compounds were chosen after high throughput screening kinase activity assays determined them as potential Lyn kinase inhibitors. Their kinase inhibitory and anti-inflammatory effect on Aβ-stimulated activation was assessed using the murine microglial cell line, BV2. Cells were treated with the compounds to determine effects on active, phosphorylated levels of Src family kinases, Src and Lyn, as well as MAP kinases ERK, JNK and p38. Only one compound, LDDN-0003499, produced a dose dependent decrease in basal levels of active, phosphorylated Src and Lyn in the BV2 cells. LDDN-0003499 treatment also attenuated the Aβ-stimulated increase in active, phosphorylated levels of Lyn/Src and TNFα and IL-6 secretion. This study identifies a novel small molecule Src family tyrosine kinase inhibitor with anti-inflammatory effects in response to Aβ stimulation of microglia. Further in vitro/in vivo characterization of LDDN-0003499 as well as structural modification may provide a new tool for attenuating microglial-mediated brain inflammatory conditions such as that occurring in AD.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4498792/pdf/Terms of Use
This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAACitable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:17820764
Collections
- HMS Scholarly Articles [17922]
Contact administrator regarding this item (to report mistakes or request changes)