Premium
Ebselen attenuates oxidative stress‐induced apoptosis via the inhibition of the c‐Jun N‐terminal kinase and activator protein‐1 signalling pathway in PC12 cells
Author(s) -
Yoshizumi Masanori,
Kogame Toshiaki,
Suzaki Yuki,
Fujita Yoshiko,
Kyaw Moe,
Kirima Kazuyoshi,
Ishizawa Keisuke,
Tsuchiya Koichiro,
Kagami Shoji,
Tamaki Toshiaki
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704808
Subject(s) - ebselen , c jun , chemistry , oxidative stress , p38 mitogen activated protein kinases , activator (genetics) , kinase , protein kinase a , programmed cell death , apoptosis , microbiology and biotechnology , biochemistry , glutathione peroxidase , biology , catalase , transcription factor , receptor , gene
Ebselen (2‐phenyl‐1,2‐benzisoselenazol‐3[2H]‐one) is a selenoorganic compound exhibiting both glutathione peroxidase activity and antioxidant activity. Although it has been reported that ebselen is effective for oxidative stress‐induced neuronal damage both in vivo and clinically, the precise mechanisms of the efficacy have not yet been elucidated. Thus, we hypothesized that ebselen may affect reactive oxygen species‐induced mitogen‐activated protein (MAP) kinase activation in cultured PC12 cells. Our findings showed that hydrogen peroxide (H 2 O 2 ) stimulated rapid and significant activation of extracellular signal‐regulated kinase (ERK)1/2, c‐Jun N‐terminal kinase (JNK) and p38 in PC12 cells, which is a model of catecholamine‐containing neurons. H 2 O 2 ‐induced JNK activation was inhibited by ebselen, whereas ERK1/2 and p38 activation by H 2 O 2 were not affected by ebselen. Inhibition by ebselen of H 2 O 2 ‐induced hydroxyl radical generation in PC12 cells was observed using electron paramagnetic resonance measurements. Ebselen also inhibited H 2 O 2 ‐induced increases in DNA binding activity of activator protein‐1 (AP‐1), a downstream transcription factor of JNK, composed of the c‐Jun homo/heterodimer. Finally, pretreatment of cells with ebselen resulted in a significant recovery from cell death including apoptosis by H 2 O 2 in PC12 cells. These findings suggest that ebselen attenuates oxidative stress‐induced neuronal cell death through the inhibition of the JNK and AP‐1 signalling pathway. Thus, inhibition of JNK by ebselen may imply its usefulness for treatment of ischaemic cerebral diseases relevant to neuronal cell death.British Journal of Pharmacology (2002) 136 , 1023–1032. doi: 10.1038/sj.bjp.0704808