Biflavonoid Methylchamaejasmin and Khaya grandifoliola Extract Inhibit NLRP3 Inflammasome in THP-1 Cell Model of Neuroinflammation.

ABSTRACT

Neuroinflammation is a common hallmark of Alzheimer's disease (AD), with NLRP3 inflammasome proven to be activated in microglia of AD patients' brains. In this study, a newly isolated biflavonoid (7,7'-di-O-methylchamaejasmin/M8) and a crude extract of the plant Khaya grandifoliola (KG) were investigated for their inhibitory effect on inflammasome activation. In preliminary experiments, M8 and KG showed no cytotoxicity on human macrophage-like differentiated THP-1 cells and exhibited anti-inflammatory inhibition of nitric oxide produced following lipopolysaccharide stimulation. Furthermore, M8 and KG blocked IL-1ß and IL-18 production by reducing NLRP3 inflammasome components including NFκB, NLRP3, Caspase-1, pro-IL-1ß, and pro-IL-18 at the mRNA and protein levels. Regarding the formation of ASC (apoptosis-associated speck-like protein containing a CARD) specks during inflammasome activation, the size and fluorescent intensity of the existing specks were unchanged across all treatment conditions. However, M8 and KG treatments were shown to prevent further speck formation. In addition, experiments on amyloid ß phagocytosis showed that M8 and KG pretreatments can restore the phagocytic activity of THP-1 cells, which was impaired following inflammasome activation. Altogether, our findings describe for the first time a promising role of biflavonoids and KG extract in preventing inflammasome activation and protecting against neuroinflammation, a key factor in AD development.