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NPC to the peri-infarct cortex was also observed in adult mice
stroke models. Thus a clear role for coordinated Epo signaling in
early brain development is evident.
5.2 Neuroprotection
by Epo In Vitro
Different neural cells express Epo and the EpoR including neu-
rons, astrocytes, and oligodendrocytes (
6, 74, 86, 87
). Epo appears
to be mainly produced by astrocytes (
4, 88
), while EpoR is
expressed by neurons (
43
). During injury however it seems all cells
are capable of upregulating the Epo signaling cascade eliciting both
autocrine and paracrine effects (see Fig.
2
, pathway 7).
Epo was shown to protect neurons from hypoxic and toxic
insults in different cell culture and ex vivo models (see Fig.
2
, path-
way 6). Epo supplementation counteracted hypoxia-induced cell
death in cortical and hippocampal neurons (
89-91
) and protected
PC12 cells from serum withdrawal (
92
). In toxicity models Epo
pretreatment protected hippocampal and cortical neurons from
glutamate (
93
) and NMDA exposure (
46
), ketamin cytotoxicity
(
94
), kainate-induced excitocytotoxicity in cultured spinal neurons
(
95
), as well as SH-SY5Y neuroblastoma cells from staurosprine-
induced cell death (
96
) to name but a few. Supplementation of
Epo also increased neuronal survival during oxygen glucose depri-
vation, the in vitro model for hypoxic-ischemia (
88
). Epo has also
been suggested to contribute to myelin recovery by enhancing
generation, proliferation, and differentiation of oligodendrocytes
after ischemic injury (
97, 98
) and inflammatory injury (
99
).
Generally Epo protects neuronal cells by regulating the balance
between proapoptotic and antiapoptotic pathways. Similar to eryth-
roid cells, a major mechanism occurs through JAK2/STAT activa-
tion and induction of PI3K/Akt pathways that inhibit the
pro-apoptotic protein Bad and prevent release of cytochrome c and
caspase activation (see Fig.
1
). Akt activation also inhibits glycogen
synthase kinase 3 (GSK3) (
94
) resulting in inhibition of the mito-
chondrial permeability transition pore, a major determinant of cell
death, through caspase activation. However inhibition of Akt only
partially prevented neuroprotection suggesting the contribution of
additional signaling mechanisms (
89
). A unique pathway for Epo-
mediated neuroprotection in the brain seems to be induction of
crosstalk between JAK2 and NFkB signaling cascades (see Fig.
1
).
EpoR mediated activation of JAK2 led to phosphorylation of IkB,
subsequent nuclear translocation of NFkB, and NFkB-dependent
transcription of neuroprotective genes (
88, 100
). Accordingly trans-
fection of cerebrocortical neurons with a dominant interfering form
of JAK2, or an IkB super-repressor, blocked Epo-mediated preven-
tion of neuronal apoptosis. Epo can also modulate the activity of
calcium channels through phospholipase C (PLC) (
101
), thereby
reducing the release of excitatory neurotransmitters and augmenting
nitric oxide production (
92, 102
). Very recent data suggests that
Epo-mediated neuroprotection is also associated with increased
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