The nonerythropoietic asialoerythropoietin protects against neonatal hypoxia-ischemia as potently as erythropoietin.
Recently, erythropoietin (EPO) and the nonerythropoietic derivative asialoEPO have been linked to tissue protection in the nervous system. In this study, we tested their effects in a model of neonatal hypoxia-ischemia (HI) in 7-day-old rats (unilateral carotid ligation and exposure to 7.7% O(2) for 50 min). EPO (10 U/g body weight = 80 ng/g; n = 24), asialoEPO (80 ng/g; n = 23) or vehicle (phosphate-buffered saline with 0.1% human serum albumin; n = 24) was injected intraperitoneally 4 h before HI. Both drugs were protective, as judged by measuring the infarct volumes, neuropathological score and gross morphological score. The infarct volumes were significantly reduced by both EPO (52%) and asialoEPO (55%) treatment, even though the plasma levels of asialoEPO had dropped below the detection limit (1 pm) at the onset of HI, while those of EPO were in the nanomolar range. Thus, a brief trigger by asialoEPO before the insult appears to be sufficient for protection. Proteomics analysis after asialoEPO treatment alone (no HI) revealed at least one differentially up-regulated protein, synaptosome-associated protein of 25 kDa (SNAP-25). Activation (phosphorylation) of ERK was significantly reduced in asialoEPO-treated animals after HI. EPO and the nonerythropoietic asialoEPO both provided significant and equal neuroprotection when administered 4 h prior to HI in 7-day-old rats. The protection might be related to reduced ERK activation and up-regulation of SNAP-25.
Wang
Xiaoyang
X
Perinatal Center, Department of Physiology, Göteborg University, Göteborg, Sweden. xiaoyang.wang@fysiologi.gu.se
Zhu
Changlian
C
Wang
Xinhua
X
Gerwien
Jens Gammeltoft
JG
Schrattenholz
Andre
A
Sandberg
Mats
M
Leist
Marcel
M
Blomgren
Klas
K
D000818:Animals; D000831:Animals, Newborn; D001212:Asialoglycoproteins / Q000096:biosynthesis / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020520:Brain Infarction / Q000473:pathology / Q000517:prevention & control; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000096:biosynthesis / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D050825:Synaptosomal-Associated Protein 25; D016896:Treatment Outcome
D001212:Asialoglycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; C500605:asialoerythropoietin; D004921:Erythropoietin