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Maturation Phenomenon in Cerebral Ischemia V pp 177–187Cite as

Endogenous Protection Against Hypoxia/ Ischemia in the Brain via Erythropoietin

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Abstract

Tolerance to cerebral ischemia can be induced experimentally by a variety of physical or pharmacological stimuli (`ischemic preconditioning’). We propose that Hypoxia inducible factor-1 (HIF-1) is a master switch of the transcriptional response in the induction of ischemic tolerance. We postulate that erythropoietin (EPO), a key target gene of HIF-1, plays a central role in this scenario. We have modeled ischemic preconditioningin vitro(oxygen-glucose deprivation, OGD) andin vivo(focal cerebral ischemia in mice; induction of tolerance by hypoxia or desferrioxamine) and provide evidence for the following signaling cascade: HIF-1 is rapidly activated by hypoxia in astrocytes. Following HIF-1 activation, astrocytes express and release EPO. EPO activates the neuronal EPO receptor and subsequently JAK2 and thereby PI3K. PI3K deactivates BAD via Akt-mediated phosphorylation, thus inhibiting hypoxia-induced apoptosis in neurons. Our results establish EPO as an important paracrine neuroprotective mediator of ischemic preconditioning.

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Author information

Authors and Affiliations

  1. Department of Experimental Neurology and Department of Neurology, Humboldt-University, Berlin, Germany

    L. Neeb, K. Ruscher & A. Meisel

  2. Department of Neurology, Humboldt-University Berlin, Schumannstraße, 20-21, 10098, Berlin, Germany

    U. Dirnagl

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  1. L. Neeb
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  2. K. Ruscher
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  3. U. Dirnagl
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  4. A. Meisel
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Editors and Affiliations

  1. Office of Stroke Research, Foothills Medical Centre, Rm 1162, 1403-29 Street N.W., Calgary, Alberta, T2N 2T9, Canada

    Alastair M. Buchan

  2. Department of Neurosurgery, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shu, Tokyo, 180-0023, Japan

    Umeo Ito

  3. Department of Psychology, University of Alberta, Edmonton, Alberta, T6G 2E9, Canada

    Fred Colbourne

  4. Department of Neuropathology Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku 113, Tokyo, Japan

    Toshihiko Kuroiwa

  5. Laboratory of Neuropathology and Neuroanatomical Sciences, NINDS, National Institutes of Health, Bethesda, Maryland, 20892-4128, USA

    Igor Klatzo

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© 2004 Springer-Verlag Berlin Heidelberg

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Neeb, L., Ruscher, K., Dirnagl, U., Meisel, A. (2004). Endogenous Protection Against Hypoxia/ Ischemia in the Brain via Erythropoietin. In: Buchan, A.M., Ito, U., Colbourne, F., Kuroiwa, T., Klatzo, I. (eds) Maturation Phenomenon in Cerebral Ischemia V. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18713-1_17

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  • DOI: https://doi.org/10.1007/978-3-642-18713-1_17

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-540-40874-1

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