Systemic application of granulocyte-colony stimulating factor and stem cell factor exacerbates excitotoxic brain injury in newborn mice.

Abstract

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.

• Authors: Matthias Keller, Georg Simbruner, Agnieszka Górna, Martina Urbanek, Inge Tinhofer, Elke Griesmaier, Gergely Sarkozy, Leslie Schwendimann, Pierre Gressens
• Journal: Pediatric research (Pediatr Res) Vol. 59 Issue 4 Pt 1 Pg. 549-53 (Apr 2006) ISSN: 0031-3998 [Print] United States
• PMID: 16549527 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Excitatory Amino Acid Agonists
• Neuroprotective Agents
• Neurotoxins
• Stem Cell Factor
• Granulocyte Colony-Stimulating Factor
• Ibotenic Acid

Topics

• Animals
• Animals, Newborn
• Apoptosis
• Brain (cytology, drug effects, pathology)
• Brain Injuries (chemically induced)
• Dose-Response Relationship, Drug
• Excitatory Amino Acid Agonists (toxicity)
• Granulocyte Colony-Stimulating Factor (metabolism, pharmacology)
• Ibotenic Acid (toxicity)
• Mice
• Neuroprotective Agents (metabolism, pharmacology)
• Neurotoxins (toxicity)
• Stem Cell Factor (metabolism, pharmacology)