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neuronal survival (
4, 5
) highlighting the paracrine functions of
Epo (see Fig.
2
, pathway 7).
Mechanistically Epo reduced infarct volume via JAK2, ERK,
and PI3K/Akt pathways by elevating Bcl-xL and lowered both
neuronal and inducible NOS levels in neurons (
121
). Upregulation
of anti-apoptotic pathways was also observed in neonatal rodents
submitted to focal cerebral ischemia (
122
). Epo-induced VEGF
and BDNF have also been suggested to have an important role in
angiogenesis- and neurogenesis-associated brain repair in rats
treated with Epo after embolic stroke (
110
) similar to observations
from in vitro studies (
123
). Epo was also shown to inhibit iNOS
expression preventing the formation of excess NO and protecting
facial motor neurons from death (
97
).
As in other neural cells Epo protects retina against cell death
during injury but in contrast to other CNS regions where basal Epo
is located mainly to astrocytes (
4, 86
), retinal neurons may express
both Epo and EpoR (
12
). Epo prevented death of neurotrophic
factor-deprived rat retinal ganglion cells (RGCs) in vitro, rescued
axotomized RGCs in vivo, and prevented caspase-3 activation (
124
).
Recently it was demonstrated that exogenous Epo significantly
attenuates retinal neuronal cell death induced by glyoxal advanced
glycosylation end products (AGEs) by promoting antiapoptotic and
suppressing apoptotic proteins (
125
). Systemic administration of
Epo before or immediately after retinal ischemia reduced histopatho-
logical damage and promoted functional recovery (
12
). When given
therapeutically after light insult, Epo also mimicked the effect of
hypoxic preconditioning by crossing the blood-retina barrier and
preventing light-induced apoptosis via caspase-1 activation interfer-
ence (
11
). Although transgenic overexpression of Epo with consti-
tutively high levels of Epo in the retina protected photoreceptors
against light-induced degeneration, the course or extent of retinal
degeneration in genetic models was unaltered suggesting different
apoptotic mechanisms exist (
126
).
Overall current evidence suggests that similar to erythroid
cells, and as indicated by in vitro studies, phosphorylation of JAK2
is the initial step in Epo-mediated protection in the injured brain
(
9
). Subsequently, downstream signaling modulates the transcrip-
tion and activity of proteins involved in cell survival.
In contrast to its neuroprotective properties, putative regenera-
tion-enhancing effects of Epo have been less well studied. Epo was
first shown to augment the activity of choline acetyltransferase in
central cholinergic neurons in vitro and in vivo (
127
) and to
enhance dopamine generation and differentiation of neuronal pre-
cursors in hypoxia. In agreement Epo was demonstrated to act
directly on neural stem cells and promote the production of neu-
ronal progenitors in forebrain (
42
) thus suggesting a direct contri-
bution to neurogenesis after hypoxia. Epo-related functional
recovery after spinal cord injury has also been described (
119
) and
5.4 Neurotrophic
Effects of Epo
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