title: A kavalactone derivative inhibits lipopolysaccharide-stimulated iNOS induction and NO production through activation of Nrf2 signaling in BV2 microglial cells.
abstract: Neuroinflammation and oxidative stress are involved in the pathogenesis of neurodegenerative diseases such as Alzheimer's diseases and Parkinson's disease. Naturally derived kavalactones isolated from Piper methysticum (Piperaceae) have been shown to exhibit neuroprotective effects. We have previously reported that a chemically synthesized kavalactone derivative, 2',6'-dichloro-5-methoxymethyl-5,6-dehydrokawain (compound 1) protects against oxidative stress-induced neuronal cell death through activation of Nrf2 signaling. In the present study, we examined the effect of compound 1 on neuroinflammation. In BV2 microglial cells, compound 1 strongly inhibited LPS-stimulated iNOS induction and NO production, but did not affect LPS-stimulated induction of COX2. At 6h after LPS challenge, when iNOS induction was not clearly seen, treatment with LPS or compound 1 alone increased expression of heme oxygenase 1 (HO-1) whose transcription is regulated by Nrf2. When treated with both, compound 1 enhanced LPS-stimulated HO-1 induction, which was more evident at 24h after LPS treatment. Furthermore, LPS-stimulated activation of Nrf2 signaling and nuclear translocation of Nrf2 were potentiated by compound 1. The mechanism by which compound 1 activated Nrf2 signaling was supposed to be a covalent modification of the sulfhydryl groups of Keap1 by an α,β-unsaturated carbonyl group present in the compound 1. Treatment with hemin, a HO-1 inducer, and with [Ru(CO)₃Cl₂]₂, a CO donor, decreased LPS-stimulated iNOS induction and NO production. In contrast, siRNA-mediated knockdown of HO-1 expression reduced the inhibitory effect of compound 1 on LPS-stimulated iNOS induction and NO production. The compound 1 inhibited LPS-stimulated ERK phosphorylation after LPS treatment. Finally, compound 1 suppressed LPS/IFN-γ-stimulated NO production in primary microglial cells. These results suggest that compound 1 is capable of inhibiting LPS-stimulated iNOS induction and NO production via activation of Nrf2 signaling and HO-1 induction in microglial cells. Taken together, compound 1 has a potential to reduce neuroinflammation as well as oxidative stress in neurodegenerative diseases through activation of Nrf2 signaling.
authors: Department of Urology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Gifu 501-1193, Japan.
authors: Riyako
authors: R
authors: Terazawa
authors: Nozomi
authors: N
authors: Akimoto
authors: Taku
authors: T
authors: Kato
authors: Tomohiro
authors: T
authors: Itoh
authors: Yasunori
authors: Y
authors: Fujita
authors: Nanako
authors: N
authors: Hamada
authors: Takashi
authors: T
authors: Deguchi
authors: Munekazu
authors: M
authors: Iinuma
authors: Mami
authors: M
authors: Noda
authors: Yoshinori
authors: Y
authors: Nozawa
authors: Masafumi
authors: M
authors: Ito
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D007783:Lactones / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology* / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000032:analysis / Q000276:immunology* / Q000378:metabolism; D009569:Nitric Oxide / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000276:immunology*; D010396:Penicillamine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D031701:Piper / Q000737:chemistry*; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007783:Lactones; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D048049:Extracellular Signal-Regulated MAP Kinases; D010396:Penicillamine