Role of erythropoietin (Procrit) in the brain - (EPO's stimulation of neural progenitor cells seems to give support to 'chemo brain' models of mold neurotoxicity)

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Crit Rev Oncol Hematol. 2007 May 3; [Epub ahead of print]

Role of erythropoietin in the brain.

* Noguchi CT,

* Asavaritikrai P,

* Teng R,

* Jia Y.

Molecular Medicine Branch, National Institute of Diabetes &

Digestive & Kidney Diseases, National Institutes of Health, Department

of Health and Human Services, Bethesda, MD 20892-1822, USA.

Multi-tissue erythropoietin receptor (EPO-R) expression provides

for erythropoietin (EPO) activity beyond its known regulation of red

blood cell production. This review highlights the role of EPO and

EPO-R in brain development and neuroprotection. EPO-R brain expression

includes neural progenitor cells (NPC), neurons, glial cells and

endothelial cells. EPO is produced in brain in a hypoxia sensitive

manner, stimulates NPC proliferation and differentiation, and neuron

survival, and contributes to ischemic preconditioning. Mice lacking

EPO or EPO-R exhibit increased neural cell apoptosis during

development before embryonic death due to severe anemia. EPO

administration provides neural protection in animal models of brain

ischemia and trauma, reducing the extent of injury and damage.

Intrinsic EPO production in brain and EPO stimulation of endothelial

cells contribute to neuroprotection and these are of particular

importance since only low levels of EPO appear to cross the

blood-brain barrier when administered at high dose intravenously. The

therapeutic potential of EPO for brain ischemia/trauma and

neurodegenerative diseases has shown promise in early clinical trial

and awaits further validation.

PMID: 17482474 [PubMed - as supplied by publisher]

Also:

http://jeb.biologists.org/cgi/content/full/207/18/3233

Review Article

Erythropoietin and the hypoxic brain

Hugo H. Marti

Institute of Physiology and Pathophysiology, University of Heidelberg,

Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany

e-mail: hugo.marti@...

Normal tissue function in mammals depends on adequate supply of oxygen

through blood vessels. A discrepancy between oxygen supply and

consumption (hypoxia) induces a variety of specific adaptation

mechanisms at the cellular, local and systemic level. These mechanisms

are in part governed by the activation of hypoxia-inducible

transcription factors (HIF-1, HIF-2), which in turn modulate

expression of hypoxically regulated genes such as those encoding

vascular endothelial growth factor (VEGF) and erythropoietin (EPO).

EPO is a glycoprotein that is produced mainly by interstitial

fibroblasts in the kidneys of the adult and in hepatocytes in the

foetus. Released into the circulation, EPO makes its way to the bone

marrow, where it regulates red cell production by preventing apoptosis

of erythroid progenitor cells. Recently, EPO has emerged as a

multifunctional growth factor that plays a significant role in the

nervous system. Both EPO and its receptor are expressed throughout the

brain in glial cells, neurones and endothelial cells. Hypoxia and

ischaemia have been recognised as important driving forces of EPO

expression in the brain. EPO has potent neuroprotective properties in

vivo and in vitro and appears to act in a dual way by directly

protecting neurones from ischaemic damage and by stimulating

endothelial cells and thus supporting the angiogenic effect of VEGF in

the nervous system. Thus, hypoxia-induced gene products such as VEGF

and EPO might be part of a self-regulated physiological protection

mechanism to prevent neuronal injury, especially under conditions of

chronically reduced blood flow (chronic ischaemia).

In this review, I will briefly summarize the recent findings on the

molecular mechanisms of hypoxia-regulated EPO expression in general

and give an overview of its expression in the central nervous system,

its action as a growth factor with non-haematopoietic functions and

its potential clinical relevance in various brain pathologies.

Key words: hypoxia, ischaemia, neuroprotection, angiogenesis, VEGF,

preconditioning, tolerance