Biology Reference
In-Depth Information
Chapter 11
Deciphering the Intracellular Signaling of Erythropoietin
in Neuronal Cells
Murat Digicaylioglu
Abstract
The search for potential drugs to treat neurodegenerative diseases has been intense in the last two decades.
Among many candidates, erythropoietin (EPO) was identified as a potent protectant of neurons suffering
from various adverse conditions. A wide array of literature indicates that endogenous or exogenous recom-
binant human erythropoietin and its variants activate cell signaling that initiates survival-promoting events
in neurons and neuronal cells. This chapter gives an overview of the pro-survival signaling induced by
endogenous and exogenous erythropoietin in vitro and in vivo and provides methods to further investigate
the intracellular signaling. It is important to know
that
EPO is neuroprotective, but it will greatly enhance
our chances to establish EPO as a new drug candidate if we know
how
EPO protects neurons.
The descriptions below summarize our current knowledge in non-neuronal and neuronal signaling
pathways induced by EPO. The signaling pathways involved in EPO are multiple; some are well known
whereas others are still under intense investigation and few are observed in very specific cell types. It is
important to note that neuronal signaling events triggered by EPO are still incomplete and require further
research. Therefore, excellent review articles that explore specific EPO-signaling events are referenced.
Key words
JAK2, Primary neuronal cultures, Akt kinase assay, Real time PCR, Western blotting,
Immunoprecipitation
1
Introduction
Erythropoietin is a class I cytokine with a molecular mass of
30.4 kDa (
1
). In humans, circulating EPO is produced by the
hepatocytes in fetal liver and the peritubular fibroblast-like type-1
interstitial cells in the renal cortex and outer medulla of the adult
kidney (
2
). In addition, EPO is also produced in spleen, lung, and
testis. Particularly important for neuroprotection is the production
of EPO in neuronal cells, such as neurons and astrocytes (
3
). Brain
derived EPO can be detected in the cerebrospinal fluid (
4
) of
human neonates and at significantly lower levels in adults.
Circulating EPO and brain derived EPO are likely to have different
functions. Under physiological conditions the blood brain barrier
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