TY - JOUR
T1 - Inhibition of nitric oxide production and inducible nitric oxide synthase expression by a polymethoxyflavone from young fruits of Citrus unshiu in rat primary astrocytes
AU - Ihara, Hideshi
AU - Yamamoto, Hideyuki
AU - Ida, Tomoaki
AU - Tsutsuki, Hiroyasu
AU - Sakamoto, Tatsuji
AU - Fujita, Tomoyuki
AU - Okada, Toshiya
AU - Kozaki, Shunji
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
KW - Astrocytes
KW - Neuroprotective agent
KW - Nitric oxide
KW - Polymethoxyflavone
KW - Young citrus
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U2 - 10.1271/bbb.120215
DO - 10.1271/bbb.120215
M3 - Article
C2 - 23047093
AN - SCOPUS:84868553912
VL - 76
SP - 1843
EP - 1848
JO - Bioscience, Biotechnology and Biochemistry
JF - Bioscience, Biotechnology and Biochemistry
SN - 0916-8451
IS - 10
ER -