Published Online
on July 21, 2005

A more recent version of this article appeared on August 1, 2005

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Submitted on April 7, 2005
Revised on April 26, 2005
Accepted on May 2, 2005

Neonatal Hypoxia/Ischemia Is Associated With Decreased Inflammatory Mediators After Erythropoietin Administration

Yun Sun MD; John W. Calvert BS; and John H. Zhang MD, PhD^*

From the Department of Neurosurgery (Y.S., J.H.Z.), Louisiana State University Health Sciences Center, Shreveport, La, and the Department of Physiology (J.W.V., J.H.Z.) and Division of Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, Loma Linda, Calif.

^* To whom correspondence should be addressed. E-mail: johnzhang3910{at}yahoo.com.

Background and Purpose--Erythropoietin (EPO), a hematopoietic growth factor, has been shown to be neuroprotective when administered as either a pretreatment or posttreatment. This study tested the hypothesis that one of the mechanisms of protection afforded by posttreatment with recombinant human EPO (rh-EPO) is an anti-inflammatory effect via inhibition of interleukin (IL)-1.

Methods--Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 90 minutes of hypoxia (8% O₂ at 37°C). Pups were divided into the following groups: control, hypoxia/ischemia, and hypoxia/ischemia plus rh-EPO. In the rh-EPO-treated pups, rh-EPO (5 U/g body weight IP) was administered starting 24 hours after the insult and then for 2 additional days. Samples were collected at 3, 7, 14, and 21 days after the insult. IL-1 mRNA and protein levels were determined by quantitative real-time reverse transcription-polymerase chain reaction and ELISA. Tumor necrosis factor (TNF)- mRNA levels were determined by colorimetric microplate assay.

Results--rhEPO attenuated brain injury, as assessed by brain weight, and attenuated both the hypoxia/ischemia-induced increases in IL-1 mRNA and protein levels. TNF- mRNA levels did not increase at 3 to 14 days after the hypoxic/ischemic insult.

Conclusions--Administration of exogenous rh-EPO starting 24 hours after a hypoxic/ischemic insult is neuroprotective in the neonatal rat. This neuroprotective activity prevented the secondary, delayed rise in IL-1 and attenuated the infiltration of leukocytes into the ipsilateral hemisphere.

Key words: cytokines • growth factors • hypoxia • inflammation • ischemia

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