Inhibition of calcium-calmodulin-dependent phosphodiesterase (PDE1) suppresses inflammatory responses

Publication date: Available online 23 November 2019Source: Molecular and Cellular NeuroscienceAuthor(s): Jennifer J. O'Brien, James P. O'Callaghan, Diane B. Miller, Suman Chalgeri, Lawrence P. Wennogle, Robert E. Davis, Gretchen L. Snyder, Joseph P. HendrickAbstractA novel, potent, and highly specific inhibitor of calcium-calmodulin-dependent phosphodiesterases (PDE) of the PDE1 family, ITI-214, was used to investigate the role of PDE1 in inflammatory responses. ITI-214 dose-dependently suppressed lipopolysaccharide (LPS)-induced gene expression of pro-inflammatory cytokines in an immortalized murine microglial cell line, BV2 cells. RNA profiling (RNA-Seq) was used to analyze the impact of ITI-214 on the BV2 cell transcriptome in the absence and the presence of LPS. ITI-214 was found to regulate classes of genes that are involved in inflammation and cell migration responses to LPS exposure. The gene expression changes seen with ITI-214 treatment were distinct from those elicited by inhibitors of other PDEs with anti-inflammatory activity (e.g., a PDE4 inhibitor), indicating a distinct mechanism of action for PDE1. Functionally, ITI-214 inhibited ADP-induced migration of BV2 cells through a P2Y12-receptor-dependent pathway, possibly due to increases in the extent of cAMP and VASP phosphorylation downstream of receptor activation. Importantly, this effect was recapitulated in P2 rat microglial cells in vitro, indicating that these pathways are active in native microglial cells....
Source: Molecular and Cellular Neuroscience - Category: Neuroscience Source Type: research