Pretreatment with Low Doses of Erythropoietin Ameliorates Brain Damage in Periventricular Leukomalacia by Targeting Late Oligodendrocyte Progenitors: A Rat Model

Abstract

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. Objectives: 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% O₂ 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% O₂. 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% O₂ 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.

Postnatal erythropoietin treatment mitigates neural cell loss after systemic prenatal hypoxic-ischemic injury

“…Thus, to mimic a typical clinical scenario, we examined whether neonatal rhEPO treatment administered with a significant interval between the insult and treatment could reverse brain damage from a prenatal global insult and result in lasting functional improvement in the mature CNS. Neonatal rhEPO administered after prenatal TSHI reduced signs of damage, including cleaved caspase-3 activation in developing white matter through postnatal Day 9, similar to the decrease in apoptosis found in other models using prior or concurrent rhEPO treatment with injury 27,29,30,36. Neonatal rhEPO after prenatal injury also restored the number of O4-immunopositive oligodendrocytes present at postnatal Day 9, and MBP levels present at postnatal Day 24 and in adult rats, the first demonstration of rhEPO-induced improvement of oligodendrocyte function in adults after prenatal brain injury.…”

Erythropoietin Amplifies Stroke-Induced Oligodendrogenesis in the Rat

“…However, additional experiments are warranted to examine whether EPO interacts with other mitogenic factors to promote OPC proliferation. A few studies have examined the effect of EPO on oligodendrocytes after cerebral ischemia [16], [17], [33], [34]. Administration of rhEPO immediately after hypoxia-ischemia in the neonatal rat does not protect against white matter damage measured 72 h after hypoxia-ischemia [33].…”

Evaluation of the Therapeutic Benefit of Delayed Administration of Erythropoietin following Early Hypoxic-Ischemic Injury in Rodents

“…For example, treatment with Epo immediately following HI injury in P7 rat pups has been shown to reduce infarct size in cortex [31, 32, 33, 34, 35, 36, 37] and hippocampus [21, 36] as well as to reduce the volume of the lateral ventricles [36, 37]. Treatment with Epo immediately following HI injury was also found to reduce white matter damage by protecting developing pre-oligodendrocytes [38, 39] and preserving the volume of the sub-ventricular zone [40]. At the behavioral level, Epo has been shown to ameliorate later sensory/motor deficits [33, 40], as well as spatial memory deficits [35, 36, 37] in P7 HI injured rats.…”