Korean J Pediatr.
2017 Jun;60(6):181-188. 10.3345/kjp.2017.60.6.181.
Neuroprotective effects of erythropoietin against hypoxic injury via modulation of the mitogen-activated protein kinase pathway and apoptosis
- Affiliations
-
- 1Department of Pediatrics, Daegu Catholic University Medical Center, Catholic University of Daegu School of Medicine, Daegu, Korea.
- 2Department of Pediatrics, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea.
- 3Department of Pediatrics, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea. pshmom00@gmail.com
- KMID: 2383997
- DOI: http://doi.org/10.3345/kjp.2017.60.6.181
Abstract
- PURPOSE
Hypoxic-ischemic encephalopathy is a significant cause of neonatal morbidity and mortality. Erythropoietin (EPO) is emerging as a therapeutic candidate for neuroprotection. Therefore, this study was designed to determine the neuroprotective role of recombinant human EPO (rHuEPO) and the possible mechanisms by which mitogen-activated protein kinase (MAPK) signaling pathway including extracellular signal-regulated kinase (ERK1/2), JNK, and p38 MAPK is modulated in cultured cortical neuronal cells and astrocytes.
METHODS
Primary neuronal cells and astrocytes were prepared from cortices of ICR mouse embryos and divided into the normoxic, hypoxia (H), and hypoxia-pretreated with EPO (H+EPO) groups. The phosphorylation of MAPK pathway was quantified using western blot, and the apoptosis was assessed by caspase-3 measurement and terminal deoxynucleotidyl transferase dUTP nick end labeling assay.
RESULTS
All MAPK pathway signals were activated by hypoxia in the neuronal cells and astrocytes (P<0.05). In the neuronal cells, phosphorylation of ERK-1/-2 and apoptosis were significantly decreased in the H+EPO group at 15 hours after hypoxia (P<0.05). In the astrocytes, phosphorylation of ERK-1/-2, p38 MAPK, and apoptosis was reduced in the H+EPO group at 15 hours after hypoxia (P<0.05).
CONCLUSION
Pretreatment with rHuEPO exerts neuroprotective effects against hypoxic injury reducing apoptosis by caspase-dependent mechanisms. Pathologic, persistent ERK activation after hypoxic injury may be attenuateed by pretreatment with EPO supporting that EPO may regulate apoptosis by affecting ERK pathways.
Keyword
MeSH Terms
-
Animals
Anoxia
Apoptosis*
Astrocytes
Blotting, Western
Caspase 3
DNA Nucleotidylexotransferase
Embryonic Structures
Erythropoietin*
Humans
Hypoxia-Ischemia, Brain
MAP Kinase Signaling System
Mice
Mice, Inbred ICR
Mitogen-Activated Protein Kinases
Mortality
Neurons
Neuroprotection
Neuroprotective Agents*
p38 Mitogen-Activated Protein Kinases
Phosphorylation
Phosphotransferases
Protein Kinases*
Caspase 3
DNA Nucleotidylexotransferase
Erythropoietin
Mitogen-Activated Protein Kinases
Neuroprotective Agents
Phosphotransferases
Protein Kinases
p38 Mitogen-Activated Protein Kinases
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