Erythropoietin and the hypoxic brain
Institute of Physiology and Pathophysiology, University of Heidelberg, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany
e-mail: hugo.marti{at}pio1.uni-heidelberg.de
Accepted 22 April 2004
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Summary |
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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
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Introduction |
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The human EPO gene, a single-copy gene located on chromosome 7,
consists of five exons and four introns. The resulting protein is a
165-amino-acid peptide with a molecular mass of 30 kDa. EPO has four
glycosylation sites, the glycosylation of which governs the biological
half-life in the blood. The hormone is produced mainly in the adult kidney and
the foetal liver. Peritubular fibroblasts in the kidney and hepatocytes in the
liver have been identified as primary EPO-producing cells
(Fisher, 2003
). However, EPO
expression is not confined to liver and kidney, as EPO mRNA has also been
detected at comparable levels in lung, testis and brain but not in muscle,
intestine or bone marrow of rodents (Tan
et al., 1992
). In fact, Carnot and Deflandre had already suggested
in their early publication on `hemopoietin' that the brain contained a
haematopoietic activity (Carnot and
Deflandre, 1906a
). More than 60 years later, a Romanian group
presented evidence, in a series of experiments in dogs and rats, that EPO
might be produced in the brain itself
(Baciu et al., 2000
). The
physiological role of EPO in the central nervous system (CNS) remained
enigmatic though, since the contribution of brain-derived EPO for
erythropoiesis in the bone marrow appeared insignificant due to an impeded
passage through the bloodbrain barrier (BBB). To unravel whether EPO
expression in the CNS serves a local physiological function, we and others
began to study expression of EPO and its receptor, as well as their regulation
in the CNS, in various species.
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EPO and EPO receptor expression in the brain |
---|
EPO mediates its effects through binding to its cognate receptor. Thus, EPO
receptor must be expressed at the site of action in the CNS to enable EPO to
elicit biological functions. Indeed, expression of EPO receptor mRNA and
protein was demonstrated in the brain of mouse, rat, monkey and humans
(Digicaylioglu et al., 1995;
Liu et al., 1997
;
Marti et al., 1996
). RT-PCR
and immunohistochemical analysis revealed that neurones and astrocytes carry
the EPO receptor (Bernaudin et al.,
1999
,
2000
;
Siren et al., 2001b
). In
particular, the astrocytic processes surrounding the capillaries seem to
strongly express the receptor. Moreover, EPO receptor immunoreactivity was
also localised within endothelial cells
(Brines et al., 2000
). In
vitro analysis in cell culture models confirmed expression on various
endothelial cells including brain-derived endothelial cells
(Anagnostou et al., 1994
;
Yamaji et al., 1996
) as well
as on neurones and astrocytes (Bernaudin et al.,
1999
,
2000
;
Morishita et al., 1997
;
Nagai et al., 2001
). Finally,
EPO receptor was shown in cultures of human microglial cells
(Nagai et al., 2001
) and in
rat oligodendrocytes (Sugawa et al.,
2002
).
In summary, both EPO mRNA and protein are found in the brain of a variety of mammals including humans. EPO receptor is widely expressed in most cerebral cell types, including neurones, endothelial cells, microglial cells and astrocytes. Table 1 gives an overview of the cellular sites of EPO and EPO receptor expression in the CNS. All these data encouraged the investigation of mechanisms regulating expression of EPO and its receptor and the search for a physiological function of EPO in the brain.
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Oxygen-dependent regulation of EPO gene expression |
---|
Oxygen availability influences multiple steps in HIF activation, and recent
studies have suggested that at least two steps in this process are governed by
a novel mode of signal transduction involving enzymatic hydroxylation of
specific amino acid residues in the -subunit by a group of oxygenases.
In normoxia, oxygen availability enables a specific prolyl hydroxylation
within the oxygen-dependent degradation domain of HIF-
. This prolyl
hydroxylation allows binding of the von Hippel-Lindau protein (pVHL), leading
to ubiquitylation and proteasomal degradation of HIF-
subunits
(Ivan et al., 2001
;
Jaakkola et al., 2001
). Three
isoforms of the HIF prolyl hydroxylases were identified in mammalian cells and
termed prolyl hydroxylase domain enzymes (PHD13;
Bruick and McKnight, 2001
;
Epstein et al., 2001
). All
three enzymes are widely expressed but show a distinct maximal expression
pattern (Masson and Ratcliffe,
2003
). Oxygen availability also enables asparaginyl hydroxylation
of the C-terminal transactivation domain of HIF-
, blocking interaction
with transcriptional coactivators (Lando
et al., 2002b
). This event is governed by a specific asparaginyl
hydroxylase, termed factor-inhibiting HIF-1 (FIH-1;
Hewitson et al., 2002
;
Lando et al., 2002a
). All
these enzymes use dioxygen in the hydroxylation reaction. Thus, they are
active during normoxia but get inactivated during hypoxia
(Fig. 1). The lack of
hydroxylation results in stable HIF-
, which is able to form a
DNA-binding heterodimer with HIF-ß/ARNT. The formed heterodimer then
recruits the transcriptional coactivators at the transactivation domain,
enabling transcriptional activity. Thus, under normoxic conditions,
HIF-
subunits are modified by oxygen and iron-dependent prolyl and
asparaginyl hydroxylation, leading to their instability and functional
inactivation. In hypoxia, however, the PHD and FIH enzymes are inactive,
resulting in stable and active HIF-
subunits. Therefore, HIF
hydroxylases, providing a direct link between the availability of molecular
oxygen and regulation of HIF, act as direct oxygen sensors
(Lando et al., 2003
;
Pugh and Ratcliffe, 2003
). For
more details, see a recent review by Masson and Ratcliffe
(2003
).
|
In the brain, the -subunit of HIF-1 is strongly induced during
hypoxia (Chavez et al., 2000
),
and sustained elevated levels of HIF-1
(Stroka et al., 2001
) seem to
be responsible for the continuous EPO upregulation seen in this organ during
hypoxic exposure while hypoxic EPO expression in the kidney is attenuated
(Chikuma et al., 2000
).
Depending on the severity of hypoxia, EPO mRNA levels increase between 3- and
20-fold in the brain compared with up to 200-fold induction in the kidney
(Marti et al., 1996
). Thus,
hypoxic EPO gene activation in the brain appears to occur in a very
similar way to in the kidney, albeit induction levels are lower.
On a cellular level, primary mouse astrocytes cultured in vitro
upregulate EPO expression 100-fold in response to hypoxic exposure
(Marti et al., 1996), and
EPO gene expression is also stimulated by hypoxia in neurones
(Bernaudin et al., 2000
). By
contrast, EPO receptor gene transcription is not directly influenced
by exposure to systemic hypoxia in vivo
(Digicaylioglu et al., 1995
),
but upregulation of its mRNA upon hypoxic exposure has been demonstrated in
hippocampal neurones cultured in vitro
(Lewczuk et al., 2000
).
Furthermore, anaemic stress and ischaemic conditions both enhanced EPO
receptor expression in vivo
(Bernaudin et al., 1999
),
ensuring an increased sensitivity of neuronal cells to EPO during these stress
situations (Chin et al., 2000
;
Sadamoto et al., 1998
).
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Physiological role of EPO expression in the CNS |
---|
In 1998, Sasaki and colleagues provided good evidence that endogenous
brain-derived EPO is also crucial for neuronal survival in vivo.
Infusion of a soluble EPO receptor into the brain of gerbils submitted to a
mild ischaemia that did not produce neuronal damage by itself resulted in
neuronal cell death in the hippocampus
(Sakanaka et al., 1998). These
results indicate that brain-derived EPO may be an endogenous protective agent
for neurones against mild forms of tissue hypoxia and ischaemia. Indeed, a
crucial role for the endogenous EPO/EPO receptor system was also recently
demonstrated in a model of transient global retina ischaemia. Neutralisation
of endogenous EPO exacerbated ischaemic injury, supporting the role of
brain-derived EPO for survival and recovery of neurones after hypoxic and
ischaemic episodes (Junk et al.,
2002
). Along the same lines, it was also shown that HIF-1 induced
EPO expression in the hypoxic retina protected against light-induced
retinal degeneration (Grimm et al.,
2002
).
At a cellular level, EPO has been implicated in the regulation of calcium
flux in neuronal cells in vitro. Externally applied EPO to the human
neuroblastoma cell line SK-N-MC led to an increase in calcium influx
via plasma membrane T-type voltage-dependent calcium channels
(Assandri et al., 1999) and
increased calcium uptake in the pheochromocytoma cell line PC12
(Koshimura et al., 1999
;
Masuda et al., 1993
). EPO also
elevated intracellular concentrations of monoamines
(Masuda et al., 1993
) and
increased dopamine release and tyrosine hydroxylase activity in PC12 cells
(Koshimura et al., 1999
).
Finally, EPO stimulated dopamine release and enhanced potassium-induced
acetylcholine release from rat striatal slices
(Yamamoto et al., 2002
).
Recently, it was demonstrated that EPO improved synaptic transmission during
oxygen and glucose deprivation in rat hippocampal slices
(Weber et al., 2002
). Thus,
EPO might stimulate neuronal function and viability via activation of
calcium channels and release of neurotransmitters.
A second target for physiological EPO action in the brain is the
vasculature. Originally, it was demonstrated that EPO has a mitogenic and
chemotactic effect on endothelial cells derived from the human umbilical vein
and bovine adrenal capillaries (Anagnostou
et al., 1990). It has also been shown that vessel outgrowth of rat
aortic rings is stimulated by EPO (Carlini
et al., 1995
), suggesting that EPO has angiogenic properties.
Indeed, neovascularisation in vivo was stimulated in the endometrium
after EPO injection into the mouse uterine cavity
(Yasuda et al., 1998
) and in
the chick embryo chorioallantoic membrane after EPO administration
(Ribatti et al., 1999
). The
fact that brain capillary endothelial cells express two forms of EPO receptor
mRNA (Yamaji et al., 1996
)
implicates EPO in brain angiogenesis. Indeed, EPO showed a dose-dependent
mitogenic activity on brain capillary endothelial cells
(Yamaji et al., 1996
).
Finally, glial cells are additional targets for EPO action in the brain.
For example, it was demonstrated that EPO promoted the maturation and
differentiation of oligodendrocytes and the proliferation of astrocytes in
vitro (Sugawa et al.,
2002). Furthermore, EPO was shown to exert anti-apoptotic effects
on rat microglial cells in vitro. Thus, the EPO/EPO receptor system
might serve as an endogenous system to protect brain cells from damage caused
by intermittent episodes of hypoxia. Along this line, EPO has been implicated
in the mechanisms of ischaemic tolerance or preconditioning. Preconditioning
means that practically any stimulus capable of causing injury to a tissue can,
when applied below the threshold level of damage, activate endogenous
protective mechanisms and thus potentially lessen the impact of subsequent,
more severe insults (reviewed in Dirnagl
et al., 2003
). It has been shown in models of ischaemic
preconditioning both in vitro and in vivo that
hypoxia-induced EPO release from astrocytes can inhibit hypoxia-induced
apoptosis in neurones (Ruscher et al.,
2002
) and thus provide stroke tolerance
(Prass et al., 2003
).
From the data available so far, one might conclude that EPO acts at least
in a dual way, firstly by acting as a direct neurotrophic or neuroprotective
factor and, secondly, by inducing angiogenesis
(Marti et al., 2000)
(Fig. 2). Indirect neuronal
protection by EPO would be achieved by affecting endothelial cell growth and
survival. Hypoxia- or ischaemia-induced EPO might stimulate new vessel growth,
enabling the transport of more red blood cells and thereby increasing the
amount of oxygen delivered to the hypoxic tissue, which in turn counteracts
the detrimental effects of hypoxia on neurones
(Marti and Risau, 1999
).
Finally, EPO could influence neuronal survival by modulation of glial cell
activation. Thus, EPO seems to be part of an endogenous defensive system
enabling the brain to counteract detrimental effects of hypoxia and ischaemia.
A model of such a protective system in the brain is depicted in
Fig. 2. It includes operation
of various growth factors such as EPO, VEGF and others promoted by a number of
stimuli via activation of several transcription factors. Activation
of HIF-1 by tissue hypoxia is an obvious pathway, but many others might be
involved as well. Indeed, it has been shown that hypoxia-independent
activation of HIF-1 occurs, e.g. by cytokines, as well as activation of other
transcription factors such as AP-1 and nuclear factor
B (NF-
B)
by oxygen depletion.
|
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The molecular mechanisms of EPO action in the CNS |
---|
EPO may also repress cell death in neurones by activation of anti-apoptotic
genes or by suppression of caspases, as is the case in erythroid precursor
cells, where EPO maintains expression of anti-apoptotic genes such as
bcl-2 and bcl-xL (Silva
et al., 1996). Indeed, increased gene expression of XIAP
and c-IAP2, members of apoptosis-inhibitor genes, was demonstrated in
cerebrocortical cells following pre-incubation with EPO
(Digicaylioglu and Lipton,
2001
). Furthermore, infusion of EPO caused more intense expression
of bcl-xL in the hippocampal CA1 region of ischaemic gerbils than did
vehicle infusion (Wen et al.,
2002
). Taken together, these results demonstrate that EPO has
multiple protective effects in the CNS that are at least partially mediated
through upregulation of anti-apoptotic molecules
(Chong et al., 2003
).
An important issue with regard to potential therapeutic interference is the
identification of signalling pathways that mediate the protective signal of
EPO within the cell. Cell survival in haematopoietic precursor cells is
mediated by EPO receptor activation, leading to activation of Janus-tyrosine
kinase-2 (JAK2), which in turn phosphorylates molecules in several downstream
signalling pathways, including MAPK (Ras-mitogen-activated protein kinase),
phosphatidylinositol 3-kinase (PI3K)-Akt and Stat-5 (signal transducer and
activator of transcription) (Ihle,
1995). The same pathways seem to be involved in EPO-mediated
neuroprotection (for a recent review, see
Chong et al., 2003
). EPO
induced phosphorylation of Stat-5, Akt and the MAPK ERK1 in rat hippocampal
neurones. Furthermore, inhibition of MAPK and PI3K pathways largely abolished
the EPO-induced protection against hypoxia-mediated cell death in these cells
(Siren et al., 2001a
).
Recently, it was demonstrated that EPO-mediated neuroprotection may also
involve cross-talk between JAK2 and NF-
B, resulting in activation of
NF-
B signalling pathways
(Digicaylioglu and Lipton,
2001
). However, the mechanism of NF-
B activation in
EPO-mediated signalling awaits further clarification, as it was also
demonstrated that the activity of JAK2 was dispensable for induction of
NF-
B by the EPO receptor (Bittorf et
al., 2001
). Taken together, it appears that, in neurones, EPO
binding to its receptor results in phosphorylation of JAK2 and Stat-5 as well
as in activation of NF-
B. Stat-5 and NF-
B then translocate to
the nucleus and bind to DNA, promoting expression of anti-apoptotic genes
(Juul, 2002
).
With regard to endothelial functions of EPO, it is noteworthy that
endothelial cells and haematopoietic cells are believed to be derived from the
same mesenchymal precursor, the so-called haemangioblast
(Risau, 1997). This may
explain why endothelial cells carry the EPO receptor and can be stimulated by
EPO (Ribatti et al., 1999
;
Yasuda et al., 1998
). Very
recently, it was demonstrated that EPO is a potent physiological stimulus for
endothelial progenitor cell mobilisation and stimulates postnatal
neovascularisation (Heeschen et al.,
2003
). As in the case for erythroid precursor cells and neurones,
EPO also seems to be a survival factor for endothelial cells by preventing
cell injury and DNA fragmentation through activation of Akt1 and inhibition of
cytochrome c release and caspase activity
(Chong et al., 2002
). EPO
might influence endothelial cells indirectly through activation of the
VEGF/VEGF receptor (VEGFR) system. It was demonstrated that EPO-induced
proliferation of bovine aortic and glomerular endothelial cells was prevented
by a specific anti-VEGF antibody (Nitta et
al., 1999
; Victoria et al.,
1998
). Furthermore, mRNA expression for both the VEGFR-1 and
VEGFR-2 was upregulated in the aortic cells after EPO pre-treatment
(Victoria et al., 1998
).
Finally, incubation of glomerular endothelial cells with EPO resulted in a
dose-dependent release of VEGF, which was abolished by incubation with an
anti-EPO antibody (Nitta et al.,
1999
). The physiological significance of these results remains,
however, unclear, since it appears that endothelial cells, at least in
vivo, don't produce significant amounts of VEGF
(Marti and Risau, 1998
).
Furthermore, Plate and colleagues found no effect of EPO treatment on VEGFR-2
expression in cerebral slice cultures while stimulation by hypoxia or VEGF
resulted in a clear upregulation of VEGFR-2 mRNA and protein levels
(Kremer et al., 1997
). Thus,
more work is definitely needed to delineate the putative involvement of the
VEGF/VEGFR system in EPO-mediated angiogenesis. Nevertheless, it appears
likely that increased expression of EPO and its receptor in blood vessels
during cerebral ischaemia in mice
(Bernaudin et al., 1999
) as
well as in humans (Siren et al.,
2001b
) contributes to new vessel growth in the tissue area
suffering from hypoxia.
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Pathophysiology of EPO in the CNS |
---|
Upregulation of EPO and its receptor during cerebral ischaemia implicates
the EPO/EPO receptor system in the pathophysiology of ischaemic diseases
(Bernaudin et al., 1999;
Siren et al., 2001b
). Indeed,
in a model of global ischaemia, infusion of EPO into the lateral ventricles of
gerbils prevented ischaemia-induced learning disability and rescued
hippocampal CA1 neurones from lethal ischaemic damage. In line with these
results, electron microscopy showed enhanced numbers of synapses within the
hippocampal region CA1 in EPO-treated ischaemic gerbils compared with in
vehicle-treated controls (Sakanaka et al.,
1998
). Furthermore, intracerebroventricular injection of EPO
offered significant protection of neuronal tissue in focal cerebral ischaemia
models in mice and rats with permanent occlusion of the middle cerebral artery
(Bernaudin et al., 1999
;
Sadamoto et al., 1998
). The
protective effect of EPO in brain ischaemia was later confirmed in several
animal studies in vivo (Brines et
al., 2000
; Calapai et al.,
2000
). These findings clearly demonstrated that ischaemic neuronal
injury was reduced by direct or systemic administration of EPO. The fact that
a differential temporal and cellular modulation of the EPO/EPO receptor system
by ischaemia was also detected in human brain tissue
(Siren et al., 2001b
)
indicated that EPO might have a beneficial effect for the treatment of stroke
patients (see below).
The neuroprotective effect of EPO during ischaemia and the fact that EPO
affects survival of cholinergic neurones and dopamine release led to the
hypothesis that EPO may have beneficial effects in Parkinson's disease. In a
mouse model of experimental Parkinsonism, mice received intraperitoneal
injections of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), leading to
selective dopaminergic neuronal cell death. Simultaneously, mice were treated
by direct bilateral injection of EPO or saline into the brain parenchyma. The
EPO-treated mice showed a significant improvement of locomotor activity
compared with control animals. Furthermore, MPTP-induced loss of dopaminergic
neurones was prevented by EPO (Genc et
al., 2001). These results indicate that EPO can protect
dopaminergic neurones against MPTP-induced toxicity. It remains to be
established whether these results have any implications for patients suffering
from Parkinson's disease.
The potential beneficial effect of EPO treatment was subsequently tested in
other pathologies of the brain. In a model of epilepsy, seizures were induced
in mice by administration of the glutamate analogue kainic acid. Pre-treatment
with EPO for 24 h before administration of kainate significantly delayed the
onset of status epilepticus and reduced the mortality rate when compared with
controls. However, no protection from seizures was achieved by administration
of EPO 30 min before kainate exposure
(Brines et al., 2000). These
results suggest that EPO can modulate neuronal excitability rather by
activation of gene expression than due to an acute activity on glutamate
channels. The same group also demonstrated a reduction in the clinical
severity of experimental autoimmune encephalomyelitis (EAE) after systemic EPO
administration (Brines et al.,
2000
). EPO was shown to exert an anti-inflammatory effect on the
CNS in EAE by delaying the increase of the pro-inflammatory cytokines tumour
necrosis factor (TNF) and interleukin 6 (IL-6)
(Agnello et al., 2002
). As EAE
is considered to be an appropriate animal model for multiple sclerosis, EPO
might act as a protective factor in this inflammatory pathology of the CNS.
Thus, EPO may also play an important immunomodulatory role. Furthermore,
treatment with EPO proved to be effective also for brain injury. The systemic
EPO administration, started either as a pre-treatment 24 h before or up to 6 h
after impact and continued for 4 days, revealed a significant protection
associated with a marked reduction of inflammatory infiltrate in a model of
blunt brain trauma (Brines et al.,
2000
).
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Clinical impact and outlook of EPO in the CNS |
---|
An alternative strategy aims to mimic the hypoxic response of the brain by
increasing HIF-1 activity in the CNS. This approach has the advantage of
activating the whole endogenous hypoxic response of the organism. Induction of
HIF-1 could occur either specifically, with targeted inducers, through gene
therapy or through the action of hypoxia mimetics (for a recent review, see
Giaccia et al., 2003). An
example of the latter is the iron chelator and known HIF-1-inducer
desferrioxamine. Intraperitoneal administration of desferrioxamine to mice
resulted in increased EPO mRNA levels in the brain cortex
(Bernaudin et al., 2000
) and
induced tolerance against focal cerebral ischaemia in rodents that coincided
with activation of HIF-1 DNA binding and EPO gene transcription
(Prass et al., 2002
).
In summary, the primary goal, not only for stroke patients but also for
other diseases of the CNS, is to protect neural function. Imitation of brain
endogenous protective mechanisms may be the key to future successful
approaches to neuroprotection, as activation and mimicry of endogenous
mechanisms can be expected to be efficient and well tolerated
(Ehrenreich and Siren, 2001).
In this respect, EPO might be a showpiece. Originally identified as a
haematopoietic factor, EPO is expressed in the CNS, including the human brain.
Brain-derived EPO is upregulated by hypoxia, and expression of both EPO and
EPO receptor is specifically modulated during cerebral ischaemia. Furthermore,
EPO has a neuroprotective potential both in vitro and in
vivo in various animal models of CNS diseases by inhibition of apoptosis
in neurones and inducing angiogenesis. EPO eventually also modulates
inflammatory responses. Thus, hypoxically upregulated EPO is a naturally
self-regulated physiological protective mechanism in the mammalian brain,
especially during ischaemia. As EPO is also a clinically extremely well
studied and tolerated compound, its use in stroke patients is tempting.
Results from a first clinical Phase I/Phase II study are promising.
Intravenous high-dose EPO in a total of 53 stroke patients was well tolerated
and associated with an improvement in clinical outcome at one month without
any signs of elevated haematocrit levels
(Ehrenreich et al., 2002
).
Currently, a larger multi-centre study is under way. Very recently, it was
also demonstrated in animal models that EPO can protect the myocardium from
ischaemia-reperfusion injury (Cai et al.,
2003
; Calvillo et al.,
2003
), suggestive of a general protective role of EPO against
hypoxic damage in various tissues.
Taken together, all these results support the idea that EPO acts in the CNS primarily as a direct protective factor in neurones via activation of anti-apoptotic pathways. The protective effect on neurones might be supported by the action of EPO and other growth factors such as VEGF on endothelial cells, resulting in cell survival and stimulation of new vessel growth (angiogenesis), as well as on glial cells leading to modulation of inflammatory responses (Fig. 2).
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Acknowledgments |
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