Recombinant human erythropoietin offers neuroprotection through inducing endogenous erythropoietin receptor and neuroglobin in a neonatal rat model of periventricular white matter damage

Neurosci Lett. 2017 May 22:650:12-17. doi: 10.1016/j.neulet.2017.03.024. Epub 2017 Mar 27.

Abstract

Recombinant human erythropoietin (rh-EPO) has been reported to have protective effects against brain injury. The purpose of this study was to evaluate the levels of erythropoietin receptor (EPOR) and neuroglobin (Ngb) in a neonatal rat model of periventricular white matter damage (PWMD), and to identify the relationship between the two proteins. On postnatal day 3 (P3), rats underwent permanent ligation of the right common carotid artery followed by 6% O2 for 4h (HI) or sham operation and normoxic exposure (sham). Immediately after HI, rats received a single intraperitoneal injection of rh-EPO (5U/g) or saline. We assessed the expression level of Ngb and EPOR on postnatal days 5, 7, 10 and 14. EPOR in the HI rats was initially increased as compared to the sham rats at P5. Subsequently, EPOR expression decreased, but was maintained at a higher level than in sham rats from P7 to P14. In rh-EPO treated rats, the increase in EPOR was greater than in HI rats at P5. However, EPOR levels decreased sharply from P7 to P14. In HI rats, Ngb was increased compared to the sham rats from P5 to P14. Ngb levels were further upregulated after rh-EPO administration from P5 to P10 compared to HI rats. However, this upregulation decreased at P14. In conclusion, this study shows that EPOR and Ngb were upregulated, and both of them act as important coordinated neuroprotectors in rh-EPO treatment of PWMD. However, the two proteins exhibit different expression patterns.

Keywords: Erythropoietin; Erythropoietin receptor; Hypoxia-ischemia; Neuroglobin; Premature.

MeSH terms

  • Animals
  • Animals, Newborn
  • Dose-Response Relationship, Drug
  • Erythropoietin / administration & dosage*
  • Erythropoietin / genetics
  • Female
  • Globins / metabolism*
  • Leukomalacia, Periventricular / drug therapy*
  • Leukomalacia, Periventricular / metabolism*
  • Leukomalacia, Periventricular / pathology
  • Male
  • Nerve Tissue Proteins / metabolism*
  • Neuroglobin
  • Neuroprotection / drug effects
  • Neuroprotective Agents / administration & dosage*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Erythropoietin / metabolism*
  • Recombinant Proteins
  • Treatment Outcome

Substances

  • Nerve Tissue Proteins
  • Neuroglobin
  • Neuroprotective Agents
  • Receptors, Erythropoietin
  • Recombinant Proteins
  • Erythropoietin
  • Globins