Erythropoietin: Endogenous Protection of Ischemic Brain

Robert T. Mallet, Myoung Gwi Ryou, Myoung Gwi Ryou

Research output: Chapter in Book/Report/Conference proceedingChapter

8 Scopus citations

Abstract

The human brain requires uninterrupted delivery of blood-borne oxygen and nutrients to sustain its function. Focal ischemia, particularly, ischemic stroke, and global ischemia imposed by cardiac arrest disrupt the brain's fuel supply. The resultant ATP depletion initiates a complex injury cascade encompassing intracellular Ca2 + overload, glutamate excitotoxicity, oxido-nitrosative stress, extracellular matrix degradation, and inflammation, culminating in neuronal and astroglial necrosis and apoptosis, neurocognitive deficits, and even death. Unfortunately, brain ischemia has proven refractory to pharmacological intervention. Many promising treatments afforded brain protection in animal models of focal and global ischemia, but failed to improve survival and neurocognitive recovery of stroke and cardiac arrest patients in randomized clinical trials. The culprits are the blood–brain barrier (BBB) that limits transferral of medications to the brain parenchyma, and the sheer complexity of the injury cascade, which presents a daunting array of targets unlikely to respond to monotherapies. Erythropoietin is a powerful neuroprotectant capable of interrupting multiple aspects of the brain injury cascade. Preclinical research demonstrates erythropoietin's ability to suppress glutamate excitotoxicity and intracellular Ca2 + overload, dampen oxidative stress and inflammation, interrupt the apoptotic cascade, and preserve BBB integrity. However, the erythropoietin dosages required to traverse the BBB and achieve therapeutically effective concentrations in the brain parenchyma impose untoward side effects. Recent discoveries that hypoxia induces erythropoietin production within the brain and that neurons, astroglia, and cerebrovascular endothelium harbor membrane erythropoietin receptors, raise the exciting prospect of harnessing endogenous erythropoietin to protect the brain from the ravages of ischemia-reperfusion.

Original languageEnglish
Title of host publicationVitamins and Hormones
PublisherAcademic Press Inc.
Pages197-232
Number of pages36
DOIs
Publication statusPublished - 1 Jan 2017

Publication series

NameVitamins and Hormones
Volume105
ISSN (Print)0083-6729

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Keywords

  • Apoptosis
  • Blood–brain barrier
  • Cardiac arrest
  • Caspase
  • Glutamate
  • Inflammation
  • Matrix metalloproteinase
  • Reactive oxygen species
  • Stroke

Cite this

Mallet, R. T., Ryou, M. G., & Ryou, M. G. (2017). Erythropoietin: Endogenous Protection of Ischemic Brain. In Vitamins and Hormones (pp. 197-232). (Vitamins and Hormones; Vol. 105). Academic Press Inc.. https://doi.org/10.1016/bs.vh.2017.01.002