Neuroprotective effects of erythropoietin against hypoxic injury via modulation of the mitogen-activated protein kinase pathway and apoptosis.
10.3345/kjp.2017.60.6.181
- Author:
Ji Eun JEONG
1
;
Jae Hyun PARK
;
Chun Soo KIM
;
Sang Lak LEE
;
Hai Lee CHUNG
;
Woo Taek KIM
;
Eun Joo LEE
Author Information
1. Department of Pediatrics, Daegu Catholic University Medical Center, Catholic University of Daegu School of Medicine, Daegu, Korea.
- Publication Type:Original Article
- Keywords:
Erythropoietin;
Apoptosis;
Mitogen-activated protein kinases;
Brain hypoxia-ischemia;
Neuroprotection
- MeSH:
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*
- From:Korean Journal of Pediatrics
2017;60(6):181-188
- CountryRepublic of Korea
- Language:English
-
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.
