Effects of Strigolactones on NLRP3 Activation, Nitrosative Stress, and Antioxidant Mox Phenotype: In Vitro and In Silico Evidence

TL;DR

This study explores how strigolactone analogs affect inflammation and antioxidant responses in brain cells, both in experiments and through computer modeling.

Contribution

The study identifies specific strigolactone analogs that inhibit NLRP3 inflammasome and modulate antioxidant pathways in microglial cells.

Findings

Strigolactone analogs inhibit NLRP3-mediated IL-1β release in microglial cells.

EGO10 and IND show high potency in suppressing proinflammatory factors at low micromolar doses.

(S)-EGO10 has the highest binding affinity to iNOS, NLRP3, and Keap1 ligands among SL analogs.

Abstract

Phytohormones have
significant roles in redox metabolism, inflammatory
responses, and cellular survival mechanisms within the microenvironment
of the mammalian brain. Herein, we identified the mammalian molecular
targets of three representative strigolactone (SL) analogues structurally
derived from apocarotenoids and the functional equivalent of plant
hormones. All tested SL analogues have an inhibitory effect on NLRP3
inflammasome-mediated IL-1β release in murine microglial cells.
However, IND and EGO10 became prominent among them due to their high
potency at low micromolar doses. All SL analogues dose-dependently
suppressed the release and expression of proinflammatory factors.
For EGO10 and IND, IC50 values for iNOS-associated NO secretion
were as low as 1.72 and 1.02 μM, respectively. In silico analyses
revealed that (S)-EGO10 interacted with iNOS, NLRP3,
and Keap1 ligands with the highest binding affinities among all stereoisomeric
SL analogues. Although all compounds were effective in microglial
Mox phenotype polarization, 4-Br-debranone exhibited a differential
pattern for upregulating Nrf2-driven downstream enzymes.

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