tBHQ inhibits LPS-induced microglial activation via Nrf2-mediated suppression of p38 phosphorylation.
Role of microglial Nrf2 activation in preventing neuronal death caused by microglial hyperactivation is investigated by using BV-2 microglial cells as modulator and primary neurons as target. Pretreatment of microglial cells with tBHQ, a phenolic antioxidant activating Nrf2, attenuated the LPS-derived overproduction of pro-inflammatory neurotoxic mediators like TNF-alpha, IL-1beta, IL-6, PGE(2), and NO as well as the morphological changes associated with microglial hyperactivation. Pretreatment of BV-2 cells with tBHQ suppressed LPS-induced phosphorylation of p38 required for overproduction of neurotoxic mediators. Results obtained using Nrf2-specific shRNA showed that expression of Nrf2 in microglia plays a critical role in tBHQ-derived suppression of LPS-induced p38 phosphorylation and microglial hyperactivation. Conditioned culture media taken from LPS-stimulated microglia cause neuronal death. However, the conditioned media taken from tBHQ-pretreated and LPS-stimulated microglia did not cause death of primary neurons. This suggested that prior activation of Nrf2 in microglia may inhibit microglial hyperactivation and prevent neuronal death.
Koh
Kyungmi
K
School of Biological Sciences, Seoul National University, Seoul 151-742, Republic of Korea.
Cha
Youngnam
Y
Kim
Sunyoung
S
Kim
Jiyoung
J
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D019610:Cytoprotection; D006873:Hydroquinones / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000975:Antioxidants; D017077:Culture Media, Conditioned; D006873:Hydroquinones; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C018855:2-tert-butylhydroquinone; D048051:p38 Mitogen-Activated Protein Kinases