Pretreatment with low doses of erythropoietin ameliorates brain damage in periventricular leukomalacia by targeting late oligodendrocyte progenitors: a rat model.
BACKGROUND
One of the pathological hallmarks of periventricular leukomalacia (PVL) is the selective vulnerability of late oligodendrocyte progenitors (preoligodendrocytes; preOLs) to hypoxia-ischemia (H-I). It is unknown whether recombinant human erythropoietin (rhEPO) protects preOLs in vivo.


OBJECTIVE
To develop a rat PVL model in which preOLs are selectively damaged and exhibit similar pathological changes to diffuse-type human PVL, various conditions of H-I were compared in P2-P7 rats (P2 = postnatal day 2). To evaluate the effect of rhEPO on oligoprotection (preOLs), rhEPO was administered to P3 PVL rats.


METHODS
After counts of NG2-positive and O4-positive cells were performed in P2-P7 rats, right common carotid artery occlusion followed by 6% O(2) for 0-120 min was performed in P2-P4 rats. The mortality and histological alterations after hematoxylin/eosin staining and ED1 immunostaining were assessed 2 days after H-I. Various doses of rhEPO (1-30,000 U/kg i.p.) were administered to PVL rats 15 min before administration of 6% O(2).


RESULTS
Double-positive cells for NG2 and O4 were detected from P2, and their number gradually increased until P7. Although right common carotid artery occlusion with 6% O(2) for 60 min resulted in a relatively high proportion of deaths in P2-P4 rats, typical histological changes in the PVL diffuse component were found in most surviving P3 animals. With 50-100 U/kg rhEPO, the histological damage was attenuated.


CONCLUSIONS
Histological changes similar to those seen in the PVL diffuse component were induced by H-I in P3 rats, in which preOLs were gradually developing, and a low dose of rhEPO was effective in the treatment of brain damage induced by H-I.
Mizuno
Keisuke
K
Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Science, Nagoya, Japan.
Hida
Hideki
H
Masuda
Tadashi
T
Nishino
Hitoo
H
Togari
Hajime
H
D000818:Animals; D000831:Animals, Newborn; D000941:Antigens / Q000378:metabolism; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000008:administration & dosage*; D005260:Female; D006801:Humans; D002534:Hypoxia, Brain / Q000473:pathology* / Q000517:prevention & control*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000473:pathology*; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007969:Leukomalacia, Periventricular / Q000188:drug therapy / Q000473:pathology*; D009836:Oligodendroglia / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D000099216:Chondroitin Sulfate Proteoglycan 4
D000941:Antigens; D004921:Erythropoietin; D011509:Proteoglycans; D000099216:Chondroitin Sulfate Proteoglycan 4