Erythropoietin protects the developing brain against N-methyl-D-aspartate receptor antagonist neurotoxicity.
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.
Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany.
Mark
M
Dzietko
Ursula
U
Felderhoff-Mueser
Marco
M
Sifringer
Birte
B
Krutz
Petra
P
Bittigau
Friederike
F
Thor
Rolf
R
Heumann
Christoph
C
Bührer
Chrysanthy
C
Ikonomidou
Henrik H
HH
Hansen
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000503:physiopathology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000633:toxicity; D004921:Erythropoietin / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D009414:Nerve Growth Factors / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017467:Receptors, Erythropoietin / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D018691:Excitatory Amino Acid Antagonists; C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D004921:Erythropoietin; D016291:Dizocilpine Maleate; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases