title: Methoxyflavones protect cells against endoplasmic reticulum stress and neurotoxin.
abstract: Enhanced endoplasmic reticulum (ER) stress leads to cell death in various pathophysiological situations. During a search for compounds that regulate ER stress, we identified methoxyflavones, a group of flavonoids, as strong protective agents against ER stress. Analysis in mouse insulinoma MIN6 cells revealed that methoxyflavones mildly activated the eukaryotic initiation factor 2alpha and nuclear factor erythroid 2-related factor pathways, but not the XBP1 pathway, and induced downstream genes, including glucose-regulated protein (GRP) 78, a molecular chaperone in the ER. The protective effect of methoxyflavones was enhanced by agents that increase intracellular cAMP levels such as forskolin, dibutyryl-cAMP and IBMX, but suppressed by the protein kinase A (PKA) inhibitor H-89, suggesting involvement of the PKA pathway in the regulation of ER stress by methoxyflavones. Consistent with the results in cultured cells, pretreatment of mice with tangeretin, a methoxyflavone, enhanced expression of GRP78 and HO-1 without causing ER stress in renal tubular epithelium and prevented tunicamycin-induced cell death. Furthermore, preadministration of tangeretin in mice enhanced expression of GRP78 in the substantia nigra pars compacta and protected dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin that induces both oxidative and ER stress. These results suggest that methoxyflavones play an important role in the regulation of ER stress and could be a therapeutic target for the ER stress-related diseases.
authors.affiliation: Department of Neuroanatomy, Kanazawa University Graduate School of Medical Science, 13-1 Takara-Machi, Kanazawa City, Ishikawa 920-8640, Japan.
authors.forename: Katsura
authors.initials: K
authors.lastname: Takano
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tabata
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kitao
authors.forename: Rika
authors.initials: R
authors.lastname: Murakami
authors.forename: Hiroto
authors.initials: H
authors.lastname: Suzuki
authors.forename: Masashi
authors.initials: M
authors.lastname: Yamada
authors.forename: Munekazu
authors.initials: M
authors.lastname: Iinuma
authors.forename: Yukio
authors.initials: Y
authors.lastname: Yoneda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Hori
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019610:Cytoprotection; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D047309:Flavones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism; D051379:Mice; D050983:NF-E2 Transcription Factor / Q000378:metabolism; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018384:Oxidative Stress / Q000502:physiology*; D010300:Parkinson Disease / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D047309:Flavones; D005419:Flavonoids; C000717248:Hspa5 protein, mouse; D050983:NF-E2 Transcription Factor; D009498:Neurotoxins; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C059006:tangeretin