Systemic application of granulocyte-colony stimulating factor and stem cell factor exacerbates excitotoxic brain injury in newborn mice.
Granulocyte-colony stimulating factor (G-CSF) has been shown to reduce brain lesion size and mortality in adult mice after hypoxic-ischemic injury. Another hematopoietic growth factor, stem cell factor (SCF), has been shown to be up-regulated in the brains of adult rodents following brain damage, where it stimulates postlesional neurogenesis. Injection of the excitotoxic agent ibotenate into the brain of newborn mice produces a brain lesion characterized by neuronal death and white matter cysts, which is similar to periventricular leucomalacia. The aim of the present study was to investigate whether administration of SCF and G-CSF is neuroprotective against ibotenate lesions in neonatal mice. Contrary to our expectations, cortical and white matter brain lesions induced by ibotenate were enhanced following the administration of 50 microg/kg SCF or 200 microg/kg G-CSF. Dose-response studies indicated that G-CSF could increase grey matter lesions even at lower dosages (22 and 66 microg/kg). Administration of SCF and G-CSF in combination also increased cortical and white matter lesions, to 133 +/- 8% and 187 +/- 12%. In the undamaged brain, G-CSF or G-CSF+SCF treatment had no effect on apoptosis in the grey or white matter; however, these treatments significantly increased apoptosis in the damaged brain. Our data clearly demonstrate that G-CSF and SCF are not neuroprotective and result in deleterious enhancement of excitotoxic brain damage in newborn mice. We conclude that G-CSF and SCF should be used cautiously in newborn infants with brain lesions; if they are used, long term neurologic and neurodevelopmental follow-up is warranted.
Keller
Matthias
M
Department of Neonatology, Medical University Innsbruck, Austria. Matthias.Keller@uklibk.ac.at
Simbruner
Georg
G
Górna
Agnieszka
A
Urbanek
Martina
M
Tinhofer
Inge
I
Griesmaier
Elke
E
Sarkozy
Gergely
G
Schwendimann
Leslie
L
Gressens
Pierre
P
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D001930:Brain Injuries / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D007051:Ibotenic Acid / Q000633:toxicity*; D051379:Mice; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity*; D019089:Stem Cell Factor / Q000378:metabolism / Q000494:pharmacology
D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D009498:Neurotoxins; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D007051:Ibotenic Acid