The Plant‐Derived Chalcone 2,2′,5′‐Trihydroxychalcone Provides Neuroprotection against Toll‐Like Receptor 4 Triggered Inflammation in Microglia

Abstract

Chalcones are plant metabolites with potential for therapeutic exploitation as antioxidant, anti-inflammatory, and antiproliferative agents. Here we explored the neuroprotective effects of 2,2′,5′-trihydroxychalcone (225THC), a potent antioxidant with radical-scavenging properties. 225THC was found to be a potent inhibitor of apoptosis in stimulated primary rat neuronal cultures. This was likely mediated by an anti-inflammatory effect on microglial cells since 225THC inhibited LPS-stimulated TNF-α and IL-6 secretion from primary rat microglia and modulated the cytokine/chemokine profile of BV2 microglial cells. Additionally, 225THC inhibited LPS-evoked inducible nitric oxide synthase expression but did not influence endogenous superoxide generation. Microglial flow cytometric analyses indicated the 225THC treatment induced a shift from an M1-like phenotype to a more downregulated microglial profile. Taken together these data suggest that the chalcone 2,2′,5′-trihydroxychalcone can modulate neuroinflammatory activation in brain-derived microglia and holds promise as a therapeutic in neuroinflammatory conditions.

Chalcones – Features, Identification Techniques, Attributes and Application in Agriculture

“…CHS plays role not only in the development process in many plants but also is induced under stress conditions, like UV, wounding, herbivory and microbial pathogens, resulting in the production of secondary metabolites e.g. phenolic compounds [15,16]. Chalcone is a common simple scaffold found in many naturally occurring compounds but large number of new chalcone structures have been synthesized over the years [17].…”

Chalcones—Features, Identification Techniques, Attributes, and Application in Agriculture

“…In higher plants, these compounds are biosynthesized through the action of the enzyme chalcone synthase (CHS, EC2.3.1.74), which converts one molecule of p-coumaroyl-CoA and three molecules of malonyl-CoA. CHS is not only crucial not only for plant development but is also activated under stress conditions such as UV exposure, wounding, and herbivory and microbial attacks, leading to the synthesis of secondary metabolites like phenolic compounds [15,16]. Chalcones, with their simple structural scaffold, are found in many naturally occurring compounds, but a large number of novel chalcone structures have also been synthesized over the years [17].…”

Modulation of the Innate Immune Response by Targeting Toll-like Receptors: A Perspective on Their Agonists and Antagonists

“…308 2,2′,5′-Trihydroxychalcone (2,2′,5′-THC, 115) is a ROS scavenger that downregulates TLR4 expression and inhibits apoptosis in stimulated primary rat neuronal cultures by reducing TNF-α and IL-6 secretion. 309 Phytocompounds from licorice showed interesting neuroprotective properties via inhibition of the TLR4 signaling pathway. For example, isoliquiritigenin (116) pretreatment in KA-induced epileptic rats reduced the release of CCL3, TNFα, and IL-1β; moreover, the blockade of MyD88 signaling attenuated KA-induced neuroinflammation and neuronal damage in the hippocampus.…”

“…In an AD model, the mechanism of action of hesperetin ( 114 ) was shown to be related to the modulation of TLR4/Nrf2/NF-κB signaling, providing a new therapeutic opportunity in AD . 2,2′,5′-Trihydroxychalcone (2,2′,5′-THC, 115 ) is a ROS scavenger that downregulates TLR4 expression and inhibits apoptosis in stimulated primary rat neuronal cultures by reducing TNF-α and IL-6 secretion . Phytocompounds from licorice showed interesting neuroprotective properties via inhibition of the TLR4 signaling pathway.…”