Erythropoietin prevents secondary brain injury induced by cortical lesion in mice: possible involvement of Nrf2 signaling pathway

Ann Clin Lab Sci. 2011 Fall;41(1):25-32.

Abstract

Erythropoietin (EPO) has demonstrated neuroprotective effects against traumatic brain injury (TBI), but the underlying mechanisms remain unclear. The signaling pathway of an antioxidant transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), has been shown in our previous studies to play an important role in protecting mice from TBI-induced secondary brain injury. The present study explored the effect of recombinant human erythropoietin (rhEPO) on cerebral activation of the Nrf2 signaling pathway and secondary brain injury in mice after TBI. Adult male ICR mice were randomly divided into three groups: (1) Sham group; (2) TBI group; and (3) TBI+rhEPO group (n = 12 per group). Closed head injury was performed using Hall's weight-dropping method. rhEPO was administered at a dose of 5,000 IU/kg at 30 min after TBI. Brain samples were extracted at 24 hr after the trauma. The treatment with rhEPO markedly up-regulated the mRNA expression and activities of Nrf2 and its downstream cytoprotective enzyme, NAD(P)H:quinone oxidoreductase 1 (NQO1). Administration of rhEPO also significantly ameliorated the secondary brain injury, as shown by decreased severity of neurological deficit, brain edema, and cortical apoptosis. In summary, post-TBI rhEPO administration induces Nrf2-mediated cytoprotective responses in the injured brain, and this may be a mechanism whereby rhEPO improves the outcome following TBI.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Brain Edema / complications
  • Brain Edema / pathology
  • Brain Edema / physiopathology
  • Brain Injuries / complications
  • Brain Injuries / drug therapy*
  • Brain Injuries / pathology
  • Brain Injuries / prevention & control*
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / enzymology
  • Cerebral Cortex / pathology*
  • Cerebral Cortex / physiopathology
  • DNA / metabolism
  • Erythropoietin / administration & dosage
  • Erythropoietin / pharmacology*
  • Erythropoietin / therapeutic use
  • Hand Strength / physiology
  • Humans
  • In Situ Nick-End Labeling
  • Male
  • Mice
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism*
  • Nervous System Diseases / complications
  • Nervous System Diseases / pathology
  • Nervous System Diseases / physiopathology
  • Protein Binding / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recombinant Proteins
  • Signal Transduction* / drug effects

Substances

  • NF-E2-Related Factor 2
  • RNA, Messenger
  • Recombinant Proteins
  • Erythropoietin
  • DNA
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse