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 neuroinflamm atory sequelae have been linked to the disease progression of several neuro degenerative disorders, including Alzheimer's disease. We found that the ex perimental anti-inflammatory drug K252a, an inhibitor of calmodulin regulat ed protein kinases (CaMKs). can block induction of both the oxidative stres s 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 t hat the profile of CaMKIV and CaMKII isoforms in primary cortical glial cul tures and BV-2 cells is distinct from that found in neurons. Knowledge of c ellular mechanisms and high throughput screens of a pharmacologically focus ed chemical library allowed the discovery of novel pyridazine-based compoun ds that are cell permeable ligand modulators of gene regulating protein kin ases involved in the induction of iNOS and IL-I beta in activated glia. Pyr idazine-based compounds are attractive for the development of new therapeut ics due to the retention of the remarkable pharmacological properties of K2 52a and related indolocarbazole alkaloids, and presence of enhanced functio nal selectivity in a comparatively simple structure amenable to diverse syn thetic chemistries. (C) 2001 Elsevier Science Ltd. All rights reserved.