期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：26
页码：9855-9860
DOI：10.1073/pnas.0403172101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Erythropoietin (EPO) and insulin-like growth factor I (IGF-I) are cytokines that inhibit neuronal apoptosis. However, their maximal antiapoptotic effect, even at high concentrations, is observed only when neurons are pretreated for several hours before insult. Here we show that simultaneous administration of EPO and IGF-I (EPO+IGF-I) eliminates the preincubation period required to prevent N-methyl-D-aspartate (NMDA)-induced apoptosis in cultured rat cerebrocortical neurons. The synergistic effect of EPO+IGF-I was mediated, at least in part, by activation of phosphatidylinositol 3-kinase (PI3-K). EPO+IGF-I synergistically activated Akt (protein kinase B), a downstream target of PI3-K, and prevented dephosphorylation of Akt. Overexpression of a dominant interfering form of Akt (dnAkt) abrogated EPO+IGF-I-mediated neuroprotection. EPO+IGF-I treatment did not prevent initial NMDA-induced caspase-3 activation, which was observed within 6 h of insult; however, EPO+IGF-I-treated neurons survived at least 2 days after NMDA insult. These cytokines prevented neuronal apoptosis downstream of caspase activation by facilitating association between X-linked inhibitor of apoptosis protein, an inhibitor of caspase proteolytic activity, and activated caspase-3. These results imply that EPO+IGF-I exert cooperative actions that afford acute neuroprotection via activation of the PI3-K-Akt pathway.
关键词：apoptosis ; phosphatidylinositol 3-kinase ; Akt (protein kinase B) ; X-linked inhibitor of apoptosis protein ; caspase-3
