Inhibition of CCAAT/enhancer binding protein δ expression by chrysin in microglial cells results in anti-inflammatory and neuroprotective effects

P>The control of neuroinflammation is a potential target to be considered in the treatment of neurodegenerative diseases. It is therefore important to find anti-inflammatory drugs and study new targets that inhibit neuroinflammation. We designed an experimental model of neuroinflammation in vitro to study the anti-inflammatory and neuroprotective effects of the flavonoid chrysin and the involvement of nuclear factor-kappa B p65 and CCAAT/enhancer binding proteins (C/EBPs) beta and delta transcription factors in its mechanism of action. We used primary cultures of mouse embryonic cortical neurons and cultures of BV2 (murine microglial cell line) or mouse primary microglia. We induced neuronal death in neuronal-BV2/microglial co-cultures using lipopolysaccharide of Escherichia coli and interferon-gamma. Chrysin pre-treatment inhibited nitric oxide and tumor necrosis factor-alpha production, as well as inducible nitric oxide synthase expression in lipopolysaccharide E. coli and interferon-gamma-treated microglial cells, but did not affect cyclooxygenase-2 expression. Chrysin pre-treatment also protected neurons against the neurotoxicity induced by reactive microglial cells. These effects were associated to a decrease in C/EBP delta protein level, mRNA expression, and DNA-binding activity, with no effect on C/EBP beta and p65 nuclear protein levels or DNA-binding activity, pointing out C/EBP delta as a possible mediator of chrysin effects. Consequently, C/EBP delta is a possible target to act against neuroinflammation in neurodegenerative processes.