Faim2 contributes to neuroprotection by erythropoietin in transient brain ischemia

J Neurochem. 2018 May;145(3):258-270. doi: 10.1111/jnc.14296. Epub 2018 Feb 20.


Delayed cell death in the penumbra region of acute ischemic stroke occurs through apoptotic mechanisms, making it amenable to therapeutic interventions. Fas/CD95 mediates apoptotic cell death in response to external stimuli. In mature neurons, Fas/CD95 signaling is modulated by Fas-apoptotic inhibitory molecule 2 (Faim2), which reduces cell death in animal models of stroke, meningitis, and Parkinson disease. Erythropoietin (EPO) has been studied as a therapeutic strategy in ischemic stroke. Erythropoietin stimulates the phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway, which regulates Faim2 expression. Therefore, up-regulation of Faim2 may contribute to neuroprotection by EPO. Male Faim2-deficient mice (Faim2-/- ) and wild-type littermates (WT) were subjected to 30 min of middle cerebral artery occlusion (MCAo) followed by 72 h of reperfusion. EPO was applied before (30 min) and after (24 and 48 h) MCAo. In WT mice application of EPO at a low dose (5000 U/kg) significantly reduced stroke volume, whereas treatment with high dose (90 000 U/kg) did not. In Faim2-/- animals administration of low-dose EPO did not result in a significant reduction in stroke volume. Faim2 expression as measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) increased after low-dose EPO but not with high dose. An extensive phenotyping including analysis of cerebral vessel architecture did not reveal confounding differences between the genotypes. In human post-mortem brain Faim2 displayed a differential expression in areas of penumbral ischemia. Faim2 up-regulation may contribute to the neuroprotective effects of low-dose erythropoietin in transient brain ischemia. The dose-dependency may explain mixed effects of erythropoietin observed in clinical stroke trials.

Keywords: Fas-apoptotic inhibitory molecule 2; dose-dependency; erythropoietin; ischemia-reperfusion; neuroprotection; stroke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Apoptosis Regulatory Proteins / metabolism*
  • Erythropoietin* / metabolism
  • Erythropoietin* / pharmacology
  • Female
  • Humans
  • Ischemic Attack, Transient / metabolism*
  • Ischemic Attack, Transient / pathology
  • Ischemic Attack, Transient / physiopathology
  • Male
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Nerve Tissue Proteins / metabolism
  • Neuroprotection / physiology*


  • Apoptosis Regulatory Proteins
  • FAIM2 protein, human
  • Membrane Proteins
  • Nerve Tissue Proteins
  • lifeguard protein, mouse
  • Erythropoietin