Endogenous Protection Against Hypoxia/ Ischemia in the Brain via Erythropoietin

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.