Comparison of anti-inflammatory potential of four different dibenzocyclooctadiene lignans in microglia; action via activation of PKA and Nrf-2 signaling and inhibition of MAPK/STAT/NF-κB pathways

ScopeThe aim of our study was to determine the signaling pathways associated with the antineuroinflammatory and neuroprotective responses induced by dibenzocyclooctadiene lignans in microglia. Methods and resultsWe employed ELISA, gelatin zymography, transient transfection, Western blot, chromatin immunoprecipitation, and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assays to characterize the effects of dibenzocyclooctadiene lignans on microglia. We found that dibenzocyclooctadiene lignans suppress TLR 2/4 agonist-induced pro-inflammatory cytokines and chemokines, PGE(2), nitric oxide, reactive oxygen species (ROS), and MMP-9 enzymatic activity through the suppression of MAPK, NF-B, and JAK-STAT activation. We next demonstrated that dibenzocyclooctadiene lignans induced the expression of phase II detoxifying/antioxidant enzymes and suppressed the iNOS and ROS activation induced by TLR 2/4 agonists. Interestingly, we also found that dibenzocyclooctadiene lignans induced PKA/CREB/Nrf-2 activation in microglia and that activation of phase II detoxifying/antioxidant enzymes via stimulation of the PKA/CREB/Nrf-2 pathway attenuated TLR 2/4 agonist-induced iNOS and ROS activation. Furthermore, dibenzocyclooctadiene lignans protected primary cortical neurons against microglia-mediated neurotoxicity. ConclusionOur findings indicate that phase II detoxifying/antioxidant enzymes and their upstream effectors, PKA/CREB/Nrf-2, play a pivotal role in the antineuroinflammatory and neuroprotective effects of dibenzocyclooctadiene lignans in TLR 2/4 agonist-stimulated microglia.