title: The nonerythropoietic asialoerythropoietin protects against neonatal hypoxia-ischemia as potently as erythropoietin.
abstract: 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.
authors.affiliation: Perinatal Center, Department of Physiology, Göteborg University, Göteborg, Sweden. xiaoyang.wang@fysiologi.gu.se
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wang
authors.forename: Changlian
authors.initials: C
authors.lastname: Zhu
authors.forename: Xinhua
authors.initials: X
authors.lastname: Wang
authors.forename: Jens Gammeltoft
authors.initials: JG
authors.lastname: Gerwien
authors.forename: Andre
authors.initials: A
authors.lastname: Schrattenholz
authors.forename: Mats
authors.initials: M
authors.lastname: Sandberg
authors.forename: Marcel
authors.initials: M
authors.lastname: Leist
authors.forename: Klas
authors.initials: K
authors.lastname: Blomgren
mesh_terms: 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
chemical_list: D001212:Asialoglycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C494210:Snap25 protein, rat; D050825:Synaptosomal-Associated Protein 25; C500605:asialoerythropoietin; D004921:Erythropoietin