http://ebm.sagepub.com/content/239/11/1461.abstract?
- Department of Integrative Physiology and Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, TX 76107-2699
- Robert T Mallet. Email: robert.mallet@unthsc.edu
-
↵* Anh Q Nguyen and Brandon H Cherry contributed equally to the preparation of this manuscript.
Abstract
Ischemic brain injury inflicted by stroke
and cardiac arrest ranks among the leading causes of death and long-term
disability
in the United States. The brain consumes large
amounts of metabolic substrates and oxygen to sustain its energy
requirements.
Consequently, the brain is exquisitely sensitive to
interruptions in its blood supply, and suffers irreversible damage
after
10–15 min of severe ischemia. Effective treatments
to protect the brain from stroke and cardiac arrest have proven elusive,
due to the complexities of the injury cascades
ignited by ischemia and reperfusion. Although recombinant tissue
plasminogen
activator and therapeutic hypothermia have proven
efficacious for stroke and cardiac arrest, respectively, these
treatments
are constrained by narrow therapeutic windows,
potentially detrimental side-effects and the limited availability of
hypothermia
equipment. Mounting evidence demonstrates the
cytokine hormone erythropoietin (EPO) to be a powerful neuroprotective
agent
and a potential adjuvant to established therapies.
Classically, EPO originating primarily in the kidneys promotes
erythrocyte
production by suppressing apoptosis of proerythroid
progenitors in bone marrow. However, the brain is capable of producing
EPO, and EPO’s membrane receptors and signaling
components also are expressed in neurons and astrocytes. EPO activates
signaling
cascades that increase the brain’s resistance to
ischemia-reperfusion stress by stabilizing mitochondrial membranes,
limiting
formation of reactive oxygen and nitrogen
intermediates, and suppressing pro-inflammatory cytokine production and
neutrophil
infiltration. Collectively, these mechanisms
preserve functional brain tissue and, thus, improve neurocognitive
recovery from
brain ischemia. This article reviews the mechanisms
mediating EPO-induced brain protection, critiques the clinical utility
of exogenous EPO to preserve brain threatened by
ischemic stroke and cardiac arrest, and discusses the prospects for
induction
of EPO production within the brain by the
intermediary metabolite, pyruvate.
No comments:
Post a Comment