Optimal neuroprotection by erythropoietin requires elevated expression of its receptor in neurons
Abstract
Erythropoietin receptor (EpoR) binding mediates neuroprotection by endogenous Epo or by exogenous recombinant human (rh)Epo. The level of EpoR gene expression may determine tissue responsiveness to Epo. Thus, harnessing the neuroprotective power of Epo requires an understanding of the Epo–EpoR system and its regulation. We tested the hypothesis that neuronal expression of EpoR is required to achieve optimal neuroprotection by Epo. The ventral limbic region (VLR) in the rat brain was used because we determined that its neurons express minimal EpoR under basal conditions, and they are highly sensitive to excitotoxic damage, such as occurs with pilocarpine-induced status epilepticus (Pilo-SE). We report that (i) EpoR expression is significantly elevated in nearly all VLR neurons when rats are subjected to 3 moderate hypoxic exposures, with each separated by a 4-day interval; (ii) synergistic induction of EpoR expression is achieved in the dorsal hippocampus and neocortex by the combination of hypoxia and exposure to an enriched environment, with minimal increased expression by either treatment alone; and (iii) rhEpo administered after Pilo-SE cannot rescue neurons in the VLR, unless neuronal induction of EpoR is elicited by hypoxia before Pilo-SE. This study thus demonstrates using environmental manipulations in normal rodents, the strict requirement for induction of EpoR expression in brain neurons to achieve optimal neuroprotection. Our results indicate that regulation of EpoR gene expression may facilitate the neuroprotective potential of rhEpo.
Acknowledgments.
We thank D. Ressnikoff and Y. Tourneur from the Centre Commun de Quantimétrie (University of Lyon 1) for their assistance in the use of the confocal microscope. This work was supported by grants from the Centre National de la Recherche Scientifique and the University of Lyon 1. P.E.S. is a fellow from the Délégation Générale pour l'Armement, Ministère Français de la Défense.
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Cover image: In this two-dimensional Gaussian core model, yellow and red represent the low- and high-potential energy states in a simple physical system. The application of techniques from computer science and information theory provides mathematical proof that a ground state has been achieved in the energy landscape. These techniques may help engineer self-assembling materials such as custom proteins or nanomaterials. See the article by Henry Cohn and Abhinav Kumar on pages 9570–9575. Image by Henry Cohn.
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© 2009.
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Received: August 1, 2008
Published online: June 16, 2009
Published in issue: June 16, 2009
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Acknowledgments
We thank D. Ressnikoff and Y. Tourneur from the Centre Commun de Quantimétrie (University of Lyon 1) for their assistance in the use of the confocal microscope. This work was supported by grants from the Centre National de la Recherche Scientifique and the University of Lyon 1. P.E.S. is a fellow from the Délégation Générale pour l'Armement, Ministère Français de la Défense.
Notes
This article contains supporting information online at www.pnas.org/cgi/content/full/0901840106/DCSupplemental.
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The authors declare no conflict of interest.
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