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Komnig, D.* ; Gertz, K.* ; Habib, P.* ; Nolte, K.W.* ; Meyer, T.* ; Brockmann, M.A.* ; Endres, M.* ; Rathkolb, B. ; Hrabě de Angelis, M. ; German Mouse Clinic Consortium* ; Schulz, J.B.* ; Falkenburger, B.H.* ; Reich, A.*

Faim2 contributes to neuroprotection by erythropoietin in transient brain ischemia.

J. Neurochem. 145, 258-270 (2018)
Verlagsversion Postprint DOI
Open Access Green
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Dose-dependency ; Erythropoietin ; Fas-apoptotic Inhibitory Molecule 2 ; Ischemia-reperfusion ; Neuroprotection ; Stroke
ISSN (print) / ISBN 0022-3042
e-ISSN 1471-4159
Quellenangaben Band: 145, Heft: 3, Seiten: 258-270 Artikelnummer: , Supplement: ,
Verlag Wiley
Begutachtungsstatus Peer reviewed