Erythropoietin is neuroprotective against NMDA-receptor-mediated excitotoxic brain injury in newborn mice.
Using an established mouse model of human periventricular leukomalacia, we investigated whether EPO could reduce excitotoxic damage. When administered 1 h following intracerebral injection of 10 microg ibotenic acid at day 5 of life, both a single injection of EPO (5000 IU/kg bw) and repetitive administrations of EPO reduced white and gray matter lesion size. The therapeutic window for protection was small as the protective effect of EPO was lost when EPO administration was delayed to 4 h post-insult. EPO-mediated upregulation of EPO-R, but not EPO, mRNA was observed within 4 h of the excitotoxic insult. The EPO effect was gender independent. Minor hematopoetic effects were observed following EPO treatment. We conclude that a single dose of EPO is sufficient to reduce excitotoxic brain injury and may therefore possess therapeutic relevance in the clinical setting.
Keller
Matthias
M
Department of Pediatrics IV, Neonatology, Neuropediatrics and Metabolic Diseases, Medical University Innsbruck, Austria, and INSERM U 676 and Service de Neurologie Pediatrique, Hopital Robert Debre 48, Paris, France. Matthias.Keller@uklibk.ac.at
Yang
Jingli
J
Griesmaier
Elke
E
Gorna
Agnieszka
A
Sarkozy
Gergely
G
Urbanek
Martina
M
Gressens
Pierre
P
Simbruner
Georg
G
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007051:Ibotenic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D007231:Infant, Newborn; D007276:Injections, Intraventricular; D007969:Leukomalacia, Periventricular / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009498:Neurotoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors*; D013997:Time Factors
D018696:Neuroprotective Agents; D009498:Neurotoxins; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D016194:Receptors, N-Methyl-D-Aspartate; D004921:Erythropoietin; D007051:Ibotenic Acid; D018698:Glutamic Acid