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caused by hypoxia-ischemia, stroke, trauma, kainate-induced
seizures, and subarachnoid hemorrhage (
29-32
).
EpoR are present on neural progenitor cells (
33
), select popu-
lations of mature neurons (
34
), astrocytes (
35
), oligodendrocytes
(
36
), microglia (
37
), and endothelial cells (
33
) within the brain.
Anti-apoptotic pathways are activated when Epo binds to cell sur-
face EpoRs, which dimerize to activate phosphorylation of Janus
kinase 2 (JAK2), phosphorylation and activation of the mitogen-
activated protein kinase (MAPK), extracellular signal-regulated
kinase (ERK1/2), as well as the phosphatidylinositol 3-kinase
(PI3K)/Akt (protein kinase B) pathway, and signal transducer and
activator of transcription 5 (STAT5) (
38
). Epo protects oligoden-
drocytes from interferon-
and LPS toxicity (
39
), improves white
matter survival in vivo (
40
) and promotes oligodendrocyte matu-
ration and differentiation in culture (
35
).
Epo promotes neuroprotection by stimulation and interaction
with other protective factors such as brain-derived neurotrophic
factor (BDNF) and glial cell derived neurotrophic factor (GDNF)
(
33, 41
). Epo actively participates in the prevention of oxidative
stress with generation of antioxidant enzymes, inhibition of nitric
oxide production, and decrease of lipid peroxidation. Long-term
survival of injured or newly generated cells may be fostered by Epo
together with vascular endothelial growth factor (VEGF) to pro-
mote angiogenesis and repair (
42, 43
). Enhanced migration of
neural progenitor cells occurs after treatment with Epo (
44
). Thus,
some protective effects of Epo are the result of direct neuronal
receptor-mediated interaction, and others are indirect. In fact, a
recent study shows there to be neuroprotective effects of Epo in
the absence of neural EpoR (
45
).
Epo crosses the intact blood-brain barrier at high dosages
(5000 U/kg i.p.) (
46
) and may cross at lower doses in the setting
of acute brain injury associated with disruption of the blood-brain
barrier (
47
). Neuroprotective Epo doses range from 300 U/kg/
dose to 30,000 U/kg, depending on the species studied, the injury
model, severity of injury, and the number of doses given (
47, 48
).
Multiple Epo treatments provide superior neuroprotection when
compared to single Epo doses following brain injury in rodent
models (
48, 49
). This is likely due to the multiple effects of Epo that
are important during the evolving injury response: Epo decreases
the early inflammatory response; decreases both early and late neu-
ronal apoptosis (
50
); and stimulates late repair processes such as
neurogenesis, angiogenesis, and migration of regenerating neurons
(
51
). Higher Epo dosages (20-30,000 U/kg), particularly when
given repeatedly, lose protective properties, may cause harm, and
are not recommended (
52
). Of note circulating blood concentra-
tions in neonates given 500-1,000 U/kg/dose are similar to those
achieved in rat pups given 5,000 U/kg/dose (
48, 53
). Complications
of Epo treatment in adults include polycythemia, rash, seizures,
γ
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