Erythropoietin protects the developing brain against N-methyl-D-aspartate receptor antagonist neurotoxicity

被引:133
作者
Dzietko, M
Felderhoff-Mueser, U
Sifringer, M
Krutz, B
Bittigau, P
Thor, F
Heumann, R
Bührer, C
Ikonomidou, C
Hansen, HH
机构
[1] Humboldt Univ, Charite, Neurosci Res Ctr, D-10117 Berlin, Germany
[2] Humboldt Univ, Charite, Dept Neonatol, Berlin, Germany
[3] Humboldt Univ, Charite, Dept Pediat Neurol, Berlin, Germany
[4] Ruhr Univ Bochum, D-4630 Bochum, Germany
[5] Danish Univ Pharmaceut Sci, Dept Pharmacol, DK-2100 Copenhagen, Denmark
关键词
NMDA receptor; apoptosis; neurodegeneration; development; neuroprotection; neurotrophin; ERK; Akt; erythropoietin; rat;
D O I
10.1016/j.nbd.2003.10.006
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Pharmacological blockade of NMDA receptor function induces apoptotic neurodegeneration in the developing rat brain. However, the use of NMDA receptor antagonists as anesthetics and sedatives represents a difficult-to-avoid clinical practice in pediatrics. This warrants the search for adjunctive neuroprotective measures that will prevent or ameliorate neurotoxicity of NMDA receptor antagonists. The NMDA receptor antagonist MK801 triggered apoptosis in the neonatal rat forebrain, most notably in cortex and thalamus. MK801 exposure reduced mRNA levels of erythropoietin (EPO) and the EPO receptor, suggesting that loss of endogenous EPO activity may contribute to MK801-induced apoptosis. Coadministration of recombinant EPO (rEPO) conferred 50% neuroprotection, partially restored MK801-induced reduction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) mRNA, and prevented decreased phosphorylation levels of extracellular signal-regulated protein kinase-1/2 (ERK1/2) and Akt. These observations indicate that rEPO partly rescues newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways. (C) 2004 Elsevier Inc. All rights reserved.
引用
收藏
页码:177 / 187
页数:11
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