論文

査読有り 国際誌
2020年5月2日

Prolonged astrocyte-derived erythropoietin expression attenuates neuronal damage under hypothermic conditions.

Journal of neuroinflammation
  • Kohki Toriuchi
  • ,
  • Hiroki Kakita
  • ,
  • Tetsuya Tamura
  • ,
  • Satoru Takeshita
  • ,
  • Yasumasa Yamada
  • ,
  • Mineyoshi Aoyama

17
1
開始ページ
141
終了ページ
141
記述言語
英語
掲載種別
DOI
10.1186/s12974-020-01831-3

BACKGROUND: Hypoxic-ischemic encephalopathy (HIE) has a high morbidity rate and involves severe neurologic deficits, including cerebral palsy. Therapeutic hypothermia (TH) has been shown to decrease the mortality rate and provide neuroprotection in infants with HIE. However, death and disability rates in HIE infants treated with TH remain high. Although the cellular mechanism of the neuroprotective effect of TH remains unclear, astrocytic erythropoietin (EPO) is known to be a key mediator of neuroprotection under hypoxic conditions. In the present study, we investigated the hypothermia effect on EPO expression in astrocytes and determined whether hypothermia attenuates neuronal damage via EPO signaling. METHODS: Astrocytes derived from rat cerebral cortex were cultured under oxygen/glucose deprivation (OGD). The expression of EPO and hypoxia-inducible factor (HIF), a transcription factor of EPO, was assessed. After OGD, astrocytes were cultured under normothermic (37 °C) or hypothermic (33.5 °C) conditions, and then EPO and HIF expression was assessed. After OGD, rat cortical neurons were cultured in astrocyte-conditioned medium (ACM) derived from the hypothermic group, and neuronal apoptosis was evaluated. RESULTS: OGD induced EPO mRNA and protein expression, although at lower levels than hypoxia alone. HIF-1α and HIF-2α protein expression increased under hypoxia alone and OGD, although OGD increased HIF-2α protein expression less than hypoxia alone. EPO gene and protein expression after OGD was significantly higher under hypothermia. Moreover, expression of HIF-1α and HIF-2α protein was enhanced under hypothermia. In the presence of ACM derived from hypothermic astrocytes following OGD, the number of cleaved caspase 3 and TdT-mediated dUTP nick-end labeling-positive apoptotic neurons was lower than in the presence of ACM from normothermic astrocytes following OGD. Blockade of EPO signaling using anti-EPO neutralization antibody attenuated the anti-apoptotic effect of ACM derived from hypothermic astrocytes following OGD. CONCLUSIONS: Hypothermia after OGD stabilized HIF-EPO signaling in astrocytes, and upregulated EPO expression could suppress neuronal apoptosis. Investigating the neuroprotective effect of EPO from astrocytes under hypothermic conditions may contribute to the development of novel neuroprotection-based therapies for HIE.

リンク情報
DOI
https://doi.org/10.1186/s12974-020-01831-3
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32359362
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195727

エクスポート
BibTeX RIS