Erythropoietin promotes neuronal replacement through revascularization and neurogenesis after neonatal hypoxia/ischemia in rats.
OBJECTIVE
Erythropoietin (EPO) has been well characterized and shown to improve functional outcomes after ischemic injury, but EPO may also have unexplored effects on neurovascular remodeling and neuronal replacement in the neonatal ischemic brain. The current study investigates the effects of exogenous administration of EPO on revascularization and neurogenesis, 2 major events thought to contribute to neuronal replacement, in the neonatal brain after hypoxia/ischemia (H/I).


METHODS
Seven-day-old rat pups were treated with recombinant human EPO or vehicle 20 minutes after H/I and again on postischemic days 2, 4, and 6. Rats were euthanized 7 or 28 days after H/I for evaluation of infarct volume, revascularization, neurogenesis, and neuronal replacement using bromodeoxyuridine incorporation, immunohistochemistry, and lectin labeling. Neurological function was assessed progressively for 28 days after H/I by gait testing, righting reflex and foot fault testing.


RESULTS
We demonstrate that exogenous EPO-enhanced revascularization in the ischemic hemisphere correlated with decreased infarct volume and improved neurological outcomes after H/I. In addition to vascular effects, EPO increased both neurogenesis in the subventricular zone and migration of neuronal progenitors into the ischemic cortex and striatum. A significant number of newly synthesized cells in the ischemic boundary expressed neuronal nuclei after EPO treatment, indicating that exogenous EPO led to neuronal replacement.


CONCLUSIONS
Our data suggest that treatment with EPO contributes to neurovascular remodeling after H/I by promoting tissue protection, revascularization, and neurogenesis in neonatal H/I-injured brain, leading to improved neurobehavioral outcomes.
Iwai
Masanori
M
Department of Neurology, University of Pittsburgh School of Medicine, 200 Lothrop Street, Pittsburgh, PA 15261, USA.
Cao
Guodong
G
Yin
Wei
W
Stetler
R Anne
RA
Liu
Jialing
J
Chen
Jun
J
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004921:Erythropoietin / Q000494:pharmacology*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009474:Neurons / Q000166:cytology* / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D020127:Recovery of Function
D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D004921:Erythropoietin