title: Inhibition of nitric oxide production and inducible nitric oxide synthase expression by a polymethoxyflavone from young fruits of Citrus unshiu in rat primary astrocytes.
abstract: Abnormal activation of astrocytes (e.g., the overproduction of cytokines and nitric oxide) is relevant to neurodegenerative disease. It is important, therefore, to search for inhibitors of the abnormal activation of astrocytes that can be derived from natural substances. This study focused on the effects of extracts from young fruits of Citrus unshiu on lipopolysaccharide (LPS)-induced nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression in rat primary astrocytes. The methanol extract of young citrus inhibited NO production in a concentration-dependent manner. After reverse-phase extraction of the extract, we found that polymethoxyflavone, nobiletin, 3,5,6,7,8,3',4'-heptamethoxyflavone, and tangeletin inhibited NO production by primary astrocytes. These polymethoxyflavones also inhibited LPS-induced iNOS protein and mRNA expression by suppressing nuclear factor-κB (NF-κB) activation and p38-mitogen-activated protein kinase (MAPK) phosphorylation. To evaluate possible applications of these neuroprotective agents in vivo, we examined the effects of young citrus fruit on delayed neurodegeneration in hippocampal CA1 neurons of the Mongolian gerbil after global ischemia. Oral administration of young citrus fruit significantly suppressed delayed neuronal death in hippocampal CA1 neurons. This suggests a possible application of young citrus fruit as a neuroprotective agent.
authors.affiliation: Department of Biological Science, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka, Japan. ihara@b.s.osakafu-u.ac.jp
authors.forename: Hideshi
authors.initials: H
authors.lastname: Ihara
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ida
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Tsutsuki
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Fujita
authors.forename: Toshiya
authors.initials: T
authors.lastname: Okada
authors.forename: Shunji
authors.initials: S
authors.lastname: Kozaki
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002957:Citrus / Q000737:chemistry*; D047309:Flavones / Q000302:isolation & purification / Q000494:pharmacology*; D005638:Fruit / Q000737:chemistry*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005849:Gerbillinae; D006624:Hippocampus / Q000166:cytology; D008070:Lipopolysaccharides / Q000494:pharmacology; D000432:Methanol / Q000737:chemistry; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D047309:Flavones; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D048051:p38 Mitogen-Activated Protein Kinases; D000432:Methanol