Ligand modulation of glial activation: cell permeable, small molecule inhibitors of serine-threonine protein kinases can block induction of interleukin 1 beta and nitric oxide synthase II.
Activated glia (astrocytes and microglia) and their associated neuroinflammatory sequelae have been linked to the disease progression of several neurodegenerative disorders, including Alzheimer's disease. We found that the experimental anti-inflammatory drug K252a, an inhibitor of calmodulin regulated protein kinases (CaMKs), can block induction of both the oxidative stress related enzyme iNOS and the proinflammatory cytokine IL-1 beta in primary cortical glial cultures and the microglial BV-2 cell line. We also found that the profile of CaMKIV and CaMKII isoforms in primary cortical glial cultures and BV-2 cells is distinct from that found in neurons. Knowledge of cellular mechanisms and high throughput screens of a pharmacologically focused chemical library allowed the discovery of novel pyridazine-based compounds that are cell permeable ligand modulators of gene regulating protein kinases involved in the induction of iNOS and IL-1 beta in activated glia. Pyridazine-based compounds are attractive for the development of new therapeutics due to the retention of the remarkable pharmacological properties of K252a and related indolocarbazole alkaloids, and presence of enhanced functional selectivity in a comparatively simple structure amenable to diverse synthetic chemistries.
Watterson
D M
DM
Drug Discovery Program, Northwestern University, 303 E Chicago Avenue, Ward 8-196, Chicago, IL 60611, USA. m-watterson@northwestern.edu
Mirzoeva
S
S
Guo
L
L
Whyte
A
A
Bourguignon
J J
JJ
Hibert
M
M
Haiech
J
J
Van Eldik
L J
LJ
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D026121:Indole Alkaloids; D007375:Interleukin-1 / Q000037:antagonists & inhibitors*; D007527:Isoenzymes / Q000378:metabolism; D008024:Ligands; D017628:Microglia / Q000201:enzymology; D009457:Neuroglia / Q000201:enzymology / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley
D002227:Carbazoles; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D007375:Interleukin-1; D007527:Isoenzymes; D008024:Ligands; C049985:staurosporine aglycone; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D017346:Protein Serine-Threonine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517686:Camk4 protein, rat