Suppression of LPS-Induced Inflammation by Chalcone Flavokawain A through Activation of Nrf2ARE-Mediated Antioxidant Genes and Inhibition of ROSNFκB Signaling Pathways in Primary Splenocytes

الملخص EN

Oxidative stress is an important contributing factor for inflammation.

Piper methysticum, also known as Kava-kava, is a shrub whose root extract has been consumed as a drink by the pacific islanders for a long time.

Flavokawain A (FKA) is a novel chalcone derived from the kava plant that is known to have medicinal properties.

This study was aimed at demonstrating the antioxidant molecular mechanisms mediated by FKA on lipopolysaccharide- (LPS-) induced inflammation in BALB/c mouse-derived primary splenocytes.

In vitro data show that the nontoxic concentrations of FKA (2-30 μM) significantly suppressed the proinflammatory cytokine (TNF-α, IL-1β, and IL-6) release but induced the secretion of interleukin-10 (IL-10), an anti-inflammatory cytokine.

It was also shown that FKA pretreatment significantly downregulated the LPS-induced ROS production and blocked the activation of the NFκB (p65) pathway leading to the significant suppression of iNOS, COX-2, TNF-α, and IL-1β protein expressions.

Notably, FKA favored the nuclear translocation of Nrf2 leading to the downstream expression of antioxidant proteins HO-1, NQO-1, and γ-GCLC via the Nrf2/ARE signaling pathway signifying the FKA’s potent antioxidant mechanism in these cells.

Supporting the in vitro data, the ex vivo data obtained from primary splenocytes derived from the FKA-preadministered BALB/c mice (orally) show that FKA significantly suppressed the proinflammatory cytokine (TNF-α, IL-1β, and IL-6) secretion in control-, LPS-, or Concanavalin A- (Con A-) stimulated cells.

A significant decrease in the ratios of pro- and anti-inflammatory cytokines (IL-6/IL-10; TNF-α/IL-10) showed that FKA possesses strong anti-inflammatory properties.

Furthermore, BALB/c mice induced with experimental pancreatitis using cholecystokinin- (CCK-) 8 showed decreased serum lipase levels due to FKA pretreatment.

We conclude that with its potent antioxidant and anti-inflammatory properties, chalcone flavokawain A could be a novel therapeutic agent in the treatment of inflammation-associated diseases.