Inhibition of Calcium-Calmodulin-Dependent Phosphodiesterase (PDE1) Suppresses Inflammatory Responses

Details

• Personal Author:
  Chalgeri S ; Davis RE ; Hendrick JP ; Miller DB ; O'Brien JJ ; O'Callaghan JP ; Snyder GL ; Wennogle LP
• Description:
  A 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. These studies are the first to demonstrate that inhibition of PDE1 exerts anti-inflammatory effects through effects on microglia signaling pathways. The ability of PDE1 inhibitors to prevent or dampen excessive inflammatory responses of BV2 cells and microglia provides a basis for exploring their therapeutic utility in the treatment of neurodegenerative diseases associated with increased inflammation and microglia proliferation such as Parkinson's disease and Alzheimer's disease. [Description provided by NIOSH]
• Subjects:
  Enzymes Immune System Laboratories Lipids Nucleotides Occupational Health Safety
• Keywords:
  Adenosines Author Keywords: Cyclic Nucleotide Brain Matter Calcium Cell Function Cell Migration Cytokines Dose Response Enzymatic Effects Enzyme Inhibitors Gene Expression Gene Regulation Immune Reaction Immune System Laboratory Animals Lipopolysaccharide Microglia Migration Phosphorylation Proteins Signaling Pathways VASP

  More +
• ISSN:
  1044-7431
• Document Type:
  Text
• Genre:
  Journal Article
• Place as Subject:
  New York ; OSHA Region 2 ; OSHA Region 3 ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  102
• NIOSHTIC Number:
  nn:20058004
• Citation:
  Mol Cell Neurosci 2020 Jan; 102:103449
• Contact Point Address:
  Gretchen L. Snyder, Intra-Cellular Therapies, Inc., The Alexandria Center for Life Sciences, 430 East 29th St Suite 900, New York, NY 10016, United States of America
• Email:
  gsnyder@intracellulartherapies.com
• CAS Registry Number:
  Calcium (CAS RN 7440-70-2)
• Federal Fiscal Year:
  2020
• NORA Priority Area:
  Manufacturing
• Peer Reviewed:
  True
• Source Full Name:
  Molecular and Cellular Neuroscience
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:5b27852616df8aa7af6189afb91800daea10e64154b6a857bae9cb0203dcb4905dbe4599c43867974f59d4dfec7de5e4603a2021aaed9d004d0384c88ccf7a26
• Download URL:
  https://stacks.cdc.gov/view/cdc/215197/cdc_215197_DS1.pdf
• File Type:
  [PDF - 1.88 MB ]