Published online August 1, 2005
PEDIATRICS
Vol. 116
No. 2
August 2005, pp.
521-522
(doi:10.1542/peds.2005-0637)
Don’t Give Up on Erythropoietin as a Neuroprotective Agent
Christof Dame, MD
Department of Neonatology
Campus Virchow-Klinikum
Charité–Universitätsmedizin Berlin
D-13353 Berlin, Germany
Hubert Fahnenstich, MD
Department of Pediatrics
Hospital of Lörrach
D-79539 Lörrach, Germany
To the Editor.—
Ohls et al1
recently reported in Pediatrics that recombinant
erythropoietin (rEpo), given in a randomized, controlled clinical trial
to reduce transfusions in extremely low birth weight (ELBW) infants,
did not significantly influence the neurodevelopmental outcome at 18 to
22 months’ corrected age. The question of the neurodevelopmental
outcome of rEpo-treated ELBW infants became of highest interest since
animal studies using a variety of models for hypoxic-ischemic brain
injury (see refs 2 and
3 for review) as well as
the first clinical trial in humans with stroke provided substantial
evidence for significant neuroprotective effects of
rEpo.4
It is indeed neither unexpected nor disappointing that ELBW infants who
received rEpo (400 U/kg body weight 3 times weekly, given intravenously
[iv] or subcutaneously [sc]) from 96 hours of age
and until the 35th postmenstrual week did not show a benefit in the
neurodevelopmental outcome. This needs additional explanation, because
specific aspects of the biology of Epo and its receptor (Epo-R) in the
central nervous system (CNS) need to be considered for future
strategies in using rEpo as a neuroprotective agent in neonates. Such
aspects concern (1) Epo-R expression, (2) endogenous Epo production,
and (3) time and dosage of rEpo treatment, particularly regarding its
transport across the blood-brain barrier (BBB).
- The Epo-R is
expressed in the human fetal, neonatal, and adult brain, but its
distribution varies between different
areas.5,6
As most precisely shown in mice, Epo-R expression is 10-fold higher in
the embryonic brain (embryonic day 13.0) than in the adult brain and
decreases significantly soon after
birth.7
However, for concepts on using rEpo as neuroprotective agent, it is
also important that Epo-R expression is up-regulated under
hypoxia.8,9
- Epo shows also a specific expression pattern in the developing and adult
human CNS.5,10
As in other organs, Epo mRNA expression is up-regulated by hypoxia or
ischemia (see ref 2 for
review), but the response of the transcriptional machinery is delayed
in the CNS. Although in the (murine) kidneys, as primary production
site of circulating Epo, mRNA levels increase to a maximum 2 hours
after the onset of hypoxia; the peak of Epo mRNA expression in the CNS
is not reached until 4
hours.11
- As shown in experimental studies, rEpo must be given in high doses at the
beginning or within a short, critical time interval after the onset of
brain injury to achieve a significant neuroprotective effect (see refs
2 and
3 for review and refs
12 and
13). Under these
conditions, a benefit may be achieved for 2 causes. Exogenous Epo may
compensate for the delayed endogenous Epo synthesis. Moreover, the
acute up-regulation of Epo-R allows a broader activation of
antiapoptotic pathways induced by Epo-R signaling. Because Epo has a
high molecular weight (34 kd), its transport across the BBB becomes a
major implication. In humans, the conclusion that Epo crosses the BBB
(perhaps depending on the degree of BBB damage or dysfunction) results
exclusively from adults, who received high-dose Epo (33000
U/day over 30 minutes iv, first treatment within 180 minutes after the
insult, for 3 days). Epo concentrations in the cerebrospinal fluid
(CSF) increased to 17.1 mU/mL (±5.6 mU/mL), which is 60 to 100
times that of adult controls but within the upper normal range of Epo
concentrations in the CSF of preterm and term infants
(<0.6–21
mU/mL).4,14
It is important to note that neonates treated with rEpo (1200 U/kg per
week sc or 1400 U/kg per week iv) do not have significantly higher Epo
concentrations in the CSF than
controls.14
Experimental studies provide evidence that rEpo crosses the BBB in
healthy adult rats by a specific and saturable
mechanism.12
More recent studies in adult rats, fetal sheep, and juvenile or adult
nonhuman primates indicate that Epo concentrations in the CSF increase
between 1 and 2 hours after systemic (intraperitoneal or iv)
application of high-dose rEpo (5000 U/kg) to concentrations of
100 mU/mL and peak between 3 and 4 hours at concentrations of
200 mU/mL.12,15
Data obtained in a rat model of neonatal hypoxic-ischemic brain injury
and in animal models of cerebral inflammation or ischemia confirm that
high rEpo doses (5000 U/kg iv or intraperitoneal) are required to
achieve neuroprotective effects if treatment is initiated after the
onset of brain
injury.12,13
Although adverse effects of high-dose rEpo treatment have not been
reported yet in animal models of neonatal brain injury, one should be
aware that data on the safety of high-dose rEpo treatment in human
neonates are not available. To achieve a fast accessibility of rEpo in
the CNS by the saturation of the mechanism transporting rEpo across the
BBB, short iv infusion may be the preferred route of rEpo application.
The risk of adverse effects may be limited by the urinary loss of rEpo
if given
iv.16
In summary, based on cumulative data, rEpo may significantly improve the
neurodevelopmental outcome of ELBW infants only if given under the
following conditions: (1) early after the onset of brain injury; (2) in
a high dose; (3) as a short intravenous infusion; and (4) repetitively
over a defined period of significant Epo-R expression. Ongoing studies
in the United States and Europe prove the safety and neuroprotective
effects of high-dose rEpo in neonates. However, the follow-up data on
the National Institute of Child Health and Human Development rEpo trial
in ELBW reported by Ohls et al are somewhat anodyne, because they show
that long-term rEpo treatment does not harm, particularly regarding the
incidence of stage III (or higher) retinopathy of prematurity
(ROP),1
which is still a major concern for high-dose rEpo treatment. Future
analysis will also require stronger criteria for evaluating
neurodevelopmental outcome, considering lower stage of ROP as well as
graded psychomotor and mental developmental indices (<70 vs
71–80).
We should not give up on the hope that rEpo may
serve in the near future as a potent neuroprotective agent in preterm
and term infants who are suffering from acute perinatal brain injury.
More data on the developmental stage and tissue-specific regulation of
Epo-R expression in the CNS, particularly under conditions such as
intraventricular hemorrhage or leukomalacia, are required to optimize
our future treatment
strategies.
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PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics
