Indirubin-3'-oxime inhibits inflammatory activation of rat brain microglia

Abstract

Microglial cells play critical roles in the immune and inflammatory responses of the brain. Under pathological conditions, the activation of microglia helps to restore brain homeostasis. However, chronic microglial activation endangers neuronal survival through the release of various proinflammatory and neurotoxic factors. As such, regulators of microglial activation have been considered as potential therapeutic candidates to reduce the risk of neurodegeneration associated with neurodegenerative diseases, including Alzheimer's and, Parkinson's diseases. Indirubin-3'-oxime, a potent inhibitor of cyclin-dependent kinases and glycogen synthase kinase-3β, has been shown to have neuroprotective potential. The specific aim of this study was to examine the efficacy of indirubin-3'-oxime in the repression of microglial activation. Indirubin-3'-oxime was shown to effectively inhibit lipopolysaccharide (LPS)-induced nitric oxide release from cultured rat brain microglia. This compound reduced the LPS-stimulated productions of tumor necrosis factor-α, interleukin-1β, prostaglandin E(2), and intracellular reactive oxygen species and also effectively reduced LPS-elicited NF-κB activation. In organotypic hippocampal slice cultures, indirubin-3'-oxime blocked LPS-related hippocampal cell death. These results suggest that indirubin-3'-oxime provides neuroprotection by reducing the productions of various neurotoxic molecules in activated microglia.