Erythropoietin is neuroprotective in a preterm ovine model of endotoxin-induced brain injury.
Intrauterine infection and inflammation have been linked to preterm birth and brain damage. We hypothesized that recombinant human erythropoietin (rhEPO) would ameliorate brain damage in anovine model of fetal inflammation. At 107 +/- 1 day of gestational age (DGA), chronically catheterized fetal sheep received on 3 consecutive days 1) an intravenous bolus dose of lipopolysaccharide ([LPS] approximately 0.9 microg/kg; n = 8); 2) an intravenous bolus dose of LPS, followed at 1 hour by 5,000 IU/kg of rhEPO (LPS + rhEPO, n = 8); or 3) rhEPO (n = 5). Untreated fetuses (n = 8) served as controls. Fetal physiological parameters were monitored, and fetal brains and optic nerves were histologically examined at 116 +/- 1 DGA. Exposure to LPS, but not to rhEPO alone or saline, resulted in fetal hypoxemia, hypotension (p < 0.05), brain damage, including white matter injury, and reductions in numbers of myelinating oligodendrocytes in the corticospinal tract and myelinated axons in the optic nerve (p < 0.05 for both). Treatment of LPS-exposed fetuses with rhEPO did not alter the physiological effects of LPS but reduced brain injury and was beneficial to myelination in the corticospinal tract and the optic nerve. This is the first study in a long-gestation species to demonstrate the neuroprotective potential of rhEPO in reducing fetal brain and optic nerve injury after LPS exposure.
Department of Anatomy and Cell Biology, University of Melbourne, Victoria, Australia. s.rees@unimelb.edu.au
Sandra
S
Rees
Nadia
N
Hale
Robert
R
De Matteo
Lisa
L
Cardamone
Mary
M
Tolcos
Michelle
M
Loeliger
Anna
A
Mackintosh
Amy
A
Shields
Megan
M
Probyn
Deanne
D
Greenwood
Richard
R
Harding
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001925:Brain Damage, Chronic / Q000188:drug therapy* / Q000382:microbiology / Q000503:physiopathology; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000139:chemically induced / Q000188:drug therapy* / Q000382:microbiology; D004731:Endotoxins / Q000633:toxicity; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005315:Fetal Diseases / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D005311:Fetal Hypoxia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000633:toxicity; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D009900:Optic Nerve / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011247:Pregnancy; D034561:Sheep, Domestic; D016896:Treatment Outcome
D004731:Endotoxins; D008070:Lipopolysaccharides; D018696:Neuroprotective Agents; D004921:Erythropoietin