Published online August 1, 2005
PEDIATRICS Vol. 116 No. 2 August 2005, pp. 521-522 (doi:10.1542/peds.2005-0637)
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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).

  1. 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
  2. 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
  3. 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.

REFERENCES

  1. Ohls RK, Ehrenkranz RA, Das A, et al. Neurodevelopmental outcome and growth at 18 to 22 months’ corrected age in extremely low birth weight infants treated with early erythropoietin and iron. Pediatrics. 2004;114 :1287 –1291[Abstract/Free Full Text]
  2. Dame C, Juul SE, Christensen RD. The biology of erythropoietin in the central nervous system and its neurotrophic and neuroprotective potential. Biol Neonate. 2001;79 :228 –235[CrossRef][Web of Science][Medline]
  3. Maiese K, Li F, Chong ZZ. New avenues of exploration for erythropoietin. JAMA. 2005;293 :90 –95[Abstract/Free Full Text]
  4. Ehrenreich H, Hasselblatt M, Dembowski C, et al. Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002;8 :495 –505[Web of Science][Medline]
  5. Siren AL, Knerlich F, Poser W, Gleiter CH, Bruck W, Ehrenreich H. Erythropoietin and erythropoietin receptor in human ischemic/hypoxic brain. Acta Neuropathol (Berl). 2001;101 :271 –276[Medline]
  6. Juul SE, Yachnis AT, Rojiani AM, Christensen RD. Immunohistochemical localization of erythropoietin and its receptor in the developing human brain. Pediatr Dev Pathol. 1999;2 :148 –158[CrossRef][Web of Science][Medline]
  7. Knabe W, Knerlich F, Washausen S, et al. Expression patterns of erythropoietin and its receptor in the developing midbrain. Anat Embryol (Berl). 2004;207 :503 –512[CrossRef][Medline]
  8. Chin K, Yu X, Beleslin-Cokic B, et al. Production and processing of erythropoietin receptor transcripts in brain. Mol Brain Res. 2000;81 :29 –42[Medline]
  9. Spandou E, Papoutsopoulou S, Soubasi V, et al. Hypoxia-ischemia affects erythropoietin and erythropoietin receptor expression pattern in the neonatal rat brain. Brain Res. 2004;1021 :167 –172[CrossRef][Web of Science][Medline]
  10. Dame C, Bartmann P, Wolber E, Fahnenstich H, Hofmann D, Fandrey J. Erythropoietin gene expression in different areas of the developing human central nervous system. Dev Brain Res. 2000;125 :69 –74[Medline]
  11. Chikuma M, Masuda S, Kobayashi T, Nagao M, Sasaki R. Tissue-specific regulation of erythropoietin production in the murine kidney, brain, and uterus. Am J Physiol Endocrinol Metab. 2000;279 :E1242 –E1248[Abstract/Free Full Text]
  12. Brines ML, Ghezzi P, Keenan S, et al. Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA. 2000;97 :10526 –10531[Abstract/Free Full Text]
  13. Wang L, Zhang Z, Wang Y, Zhang R, Chopp M. Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke. 2004;35 :1732 –1737[Abstract/Free Full Text]
  14. Juul SE, Harcum J, Li Y, Christensen RD. Erythropoietin is present in the cerebrospinal fluid of neonates. J Pediatr. 1997;130 :428 –430[CrossRef][Web of Science][Medline]
  15. Juul SE, McPherson RJ, Farrell FX, Jolliffe L, Ness DJ, Gleason CA. Erytropoietin concentrations in cerebrospinal fluid of nonhuman primates and fetal sheep following high-dose recombinant erythropoietin. Biol Neonate. 2004;85 :138 –144[CrossRef][Web of Science][Medline]
  16. Buhrer C, Obladen M, Maier R, Muller C. Urinary losses of recombinant erythropoietin in preterm infants. J Pediatr. 2003;142 :452 –453[Medline]

PEDIATRICS (ISSN 1098-4275). ©2005 by the American Academy of Pediatrics

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