This Article Full Text Full Text (PDF) All Versions of this Article: 38/10/2795    most recent STROKEAHA.107.483008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Iwai, M. Articles by Chen, J. Search for Related Content PubMed PubMed Citation Articles by Iwai, M. Articles by Chen, J. Related Collections Angiogenesis Animal models of human disease Acute Cerebral Infarction Neuroprotectors

(Stroke. 2007;38:2795.)
© 2007 American Heart Association, Inc.

Original Contributions

Erythropoietin Promotes Neuronal Replacement Through Revascularization and Neurogenesis After Neonatal Hypoxia/Ischemia in Rats

Masanori Iwai, MD; Guodong Cao, PhD; Wei Yin, MD, PhD; R. Anne Stetler, PhD; Jialing Liu, PhD Jun Chen, MD

From the Department of Neurology (M.I., G.C., W.Y., R.A.S., J.C.), University of Pittsburgh School of Medicine, Pittsburgh, Pa; the Department of Neurological Surgery (J.L.), University of California–San Francisco, San Francisco, Calif; and the Geriatric Research, Education and Clinical Center (R.A.S., J.C.), Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pa.

Correspondence to Jun Chen, MD, 507 South Biomedical Science Tower, Department of Neurology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15261. E-mail chenj2{at}upmc.edu

Background and Purpose— 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.

Key Words: erythropoietin • neonatal hypoxia/ischemia • neurogenesis • neuronal replacement • revascularization