Neonatal hypoxia/ischemia is associated with decreased inflammatory mediators after erythropoietin administration.
OBJECTIVE
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)-1beta.


METHODS
Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 90 minutes of hypoxia (8% O2 at 37 degrees 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-1beta mRNA and protein levels were determined by quantitative real-time reverse transcription-polymerase chain reaction and ELISA. Tumor necrosis factor (TNF)-alpha 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-1beta mRNA and protein levels. TNF-alpha 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-1beta and attenuated the infiltration of leukocytes into the ipsilateral hemisphere.
Sun
Yun
Y
Department of Neurosurgery, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
Calvert
John W
JW
Zhang
John H
JH
D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology; D002339:Carotid Arteries / Q000601:surgery; D004921:Erythropoietin / Q000008:administration & dosage*; D006133:Growth Substances / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D020925:Hypoxia-Ischemia, Brain / Q000473:pathology; D007249:Inflammation; D007375:Interleukin-1 / Q000378:metabolism; D007511:Ischemia; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D010100:Oxygen / Q000378:metabolism; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry / Q000627:therapeutic use; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013696:Temperature; D013997:Time Factors
D006133:Growth Substances; D007375:Interleukin-1; D012333:RNA, Messenger; D011994:Recombinant Proteins; D004921:Erythropoietin; D012313:RNA; D010100:Oxygen