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-1β 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-1β 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.
|Number of pages||10|
|State||Published - 2001|
Bibliographical noteFunding Information:
We thank Dr Thomas Lukas for his advice and technical assistance. Supported in part by grants from the Alzheimer's Association, the Institute for the Study of Aging, and National Institutes of Health Grants AG13939, AG15501 and RR13810. AW is a 2000 Bristol-Myers Squibb Academic Medicine Fellow.
- Alzheimer's disease
- Calmodulin regulated protein kinase
- Drug discovery
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience
- Cell Biology