Erythropoietin is neuroprotective against NMDA-receptor-mediated excitotoxic brain injury in newborn mice

Matthias Keller; Jingli Yang; Elke Griesmaier; Agnieszka Gorna; Gergely Sarkozy; Martina Urbanek; Pierre Gressens; Georg Simbruner

doi:10.1016/j.nbd.2006.07.007

Erythropoietin is neuroprotective against NMDA-receptor-mediated excitotoxic brain injury in newborn mice

Neurobiol Dis. 2006 Nov;24(2):357-66. doi: 10.1016/j.nbd.2006.07.007. Epub 2006 Sep 7.

Authors

Matthias Keller¹, Jingli Yang, Elke Griesmaier, Agnieszka Gorna, Gergely Sarkozy, Martina Urbanek, Pierre Gressens, Georg Simbruner

Affiliation

¹ 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

PMID: 16959492
DOI: 10.1016/j.nbd.2006.07.007

Abstract

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.

MeSH terms

Animals
Animals, Newborn
Brain / drug effects
Brain / metabolism
Brain / physiopathology
Cytoprotection / drug effects
Cytoprotection / physiology
Disease Models, Animal
Drug Administration Schedule
Erythropoietin / pharmacology*
Erythropoietin / therapeutic use
Female
Glutamic Acid / metabolism
Humans
Ibotenic Acid / antagonists & inhibitors
Ibotenic Acid / metabolism
Infant, Newborn
Injections, Intraventricular
Leukomalacia, Periventricular / drug therapy*
Leukomalacia, Periventricular / metabolism
Leukomalacia, Periventricular / physiopathology
Male
Mice
Nerve Degeneration / drug therapy*
Nerve Degeneration / physiopathology
Nerve Degeneration / prevention & control
Neuroprotective Agents / pharmacology*
Neuroprotective Agents / therapeutic use
Neurotoxins / antagonists & inhibitors*
Neurotoxins / metabolism
RNA, Messenger / drug effects
RNA, Messenger / metabolism
Receptors, Erythropoietin / genetics
Receptors, N-Methyl-D-Aspartate / agonists
Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
Time Factors

Substances

Neuroprotective Agents
Neurotoxins
RNA, Messenger
Receptors, Erythropoietin
Receptors, N-Methyl-D-Aspartate
Erythropoietin
Ibotenic Acid
Glutamic Acid