Scope: The 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 results: We 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, PGE2 , nitric oxide, reactive oxygen species (ROS), and MMP-9 enzymatic activity through the suppression of MAPK, NF-κB, 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.
Conclusion: Our 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.
Keywords: Antineuroinflammation; Dibenzocyclooctadiene lignans; Microglia; Phase II detoxifying/antioxidant enzymes; TLR 2/4 agonists.
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.