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

Neurobiology of Disease

Rolf Heumann¹  Ursula Felderhoff-Mueser¹  Petra Bittigau²  Henrik H Hansen²  Birte Krutz³  Chrysanthy Ikonomidou³  Marco Sifringer⁴  Christoph Bührer⁴  Friederike Thor⁵  Mark Dzietko⁵ 

[1]Department of Pediatric Neurology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany

[2]Department of Pharmacology, The Danish University of Pharmaceutical Sciences, DK-2100 Copenhagen, Denmark

[3]Molecular Neurobiochemistry, Ruhr University, Bochum, Germany

[4]Neuroscience Research Center, Charité, Humboldt University Berlin, Berlin, Germany

[5]Department of Neonatology, Charité, Campus Virchow Klinikum, Humboldt University Berlin, Berlin, Germany

关键词: NMDA receptor;    Apoptosis;    Neurodegeneration;    Development;    Neuroprotection;    Neurotrophin;   

DOI  :  

来源: DOAJ

【 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.

【 授权许可】

Unknown