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The Journal of Neuroscience, December 1, 2002, 22(23):10291-10301

Erythropoietin Is a Paracrine Mediator of Ischemic Tolerance in the Brain: Evidence from an In Vitro Model

Karsten Ruscher¹, Dorette Freyer¹, Maria Karsch¹, Nikolai Isaev³, Dirk Megow¹, Birgit Sawitzki², Josef Priller¹, Ulrich Dirnagl¹, and Andreas Meisel¹

Departments of ¹ Experimental Neurology and Neurology and ² Medical Immunology, Charité Hospital, Humboldt University, D-10098 Berlin, Germany, and ³ A. N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, 119899 Moscow, Russia

In an in vitro model of cerebral ischemia (oxygen glucose deprivation, OGD) we investigated whether erythropoietin (EPO) plays a critical role in ischemic preconditioning. We found that EPO time and dose-dependently induced protection against OGD in rat primary cortical neurons. Protection was significant at 5 min and reached a maximum at 48 hr after EPO application. Protection was blocked by the coapplication of a soluble Epo receptor (sEpoR) or an antibody against EpoR (anti-EpoR). Medium transfer from OGD-treated astrocytes to untreated neurons induced protection against OGD in neurons, which was attenuated strongly by the application of sEpoR and anti-EpoR. In contrast, medium transfer from OGD-treated neurons to untreated neurons induced protection against OGD that did not involve EPO. In astrocytes the OGD enhanced the nuclear translocation of hypoxia-inducible factor 1 (HIF-1), the major transcription factor regulating EPO expression. Consequently, transcription of EPO-mRNA was increased in astrocytes after OGD. Cultured neurons express EpoR, and the Janus kinase-2 (JAK-2) inhibitor AG490 abolished EPO-induced tolerance against OGD. Furthermore, EPO-induced neuroprotection as well as phosphorylation of the proapoptotic Bcl family member Bad was reduced by the phosphoinositide-3 kinase (PI3K) inhibitor LY294002. The results suggest that astrocytes challenged with OGD provide paracrine protective signals to neurons. We provide evidence for the following signaling cascade: HIF-1 is activated rapidly by hypoxia in astrocytes. After HIF-1 activation the astrocytes express and release EPO. EPO activates the neuronal EPO receptor and, subsequently, JAK-2 and thereby PI3K. PI3K deactivates BAD via Akt-mediated phosphorylation and thus may inhibit hypoxia-induced apoptosis in neurons. Our results establish EPO as an important paracrine neuroprotective mediator of ischemic preconditioning.

Key words: astrocyte; Bad; hypoxia-inducible factor-1; ischemic preconditioning; Janus kinase-2; neuron; oxygen glucose deprivation; phosphoinositol-3 kinase

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Copyright © 2002 Society for Neuroscience  0270-6474/02/222310291-11$05.00/0

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