title: Systemic G-CSF treatment does not improve long-term outcomes after neonatal hypoxic-ischaemic brain injury.
abstract: Hypoxia-ischaemia (HI) is a major factor in the pathogenesis of developmental brain injury, leading to cognitive deficits and motor disabilities in preterm infants. The haematopoietic growth factor granulocyte colony-stimulating factor (G-CSF) has been shown to exert a neuroprotective activity in rodent models of ischaemic stroke and is currently subject to phase I/II clinical trials in adults. Results of studies examining the effect of G-CSF in perinatal brain damage have been contradictory. We have previously shown that G-CSF increases NMDAR-mediated excitotoxic brain injury in the neonatal mouse brain. In this study, we evaluated the effect of G-CSF on long-term outcomes after HI. On postnatal day 5, mice pubs were first randomly assigned to a sham operation or HI and then divided into four treatment groups: i) G-CSF; ii) phosphate buffered saline (PBS) 1h after injury; iii) G-CSF and iv) PBS 60 h after injury. G-CSF (200 μg/kg BW) was administered five times within a 24h interval. Neuromotor and cognitive outcomes were assessed by open-field, novel object recognition tests and rotarod tests starting on P90, with subsequent histological analyses of brain injury. G-CSF treatment did not improve either neurobehavioural outcomes or brain injuries. Interestingly, the application of PBS and G-CSF in the acute phase increased brain damage in the hippocampus. We could not confirm the neuroprotective properties of G-CSF in neonatal HI brain damage. The exacerbation of injury by the administration of substances in the acute phase might indicate a heightened state of neurological sensitivity that is specific to mechanisms of secondary neurodegeneration and influenced by unidentified external factors possibly associated with the treatment protocol during the acute phase. This article is part of a Special Issue entitled "Interaction between repair, disease, & inflammation."
authors.affiliation: Department of Paediatrics I, University Hospital Essen, Germany.
authors.forename: G W
authors.initials: GW
authors.lastname: Schlager
authors.forename: E
authors.initials: E
authors.lastname: Griesmaier
authors.forename: K
authors.initials: K
authors.lastname: Wegleiter
authors.forename: V
authors.initials: V
authors.lastname: Neubauer
authors.forename: M
authors.initials: M
authors.lastname: Urbanek
authors.forename: U
authors.initials: U
authors.lastname: Kiechl-Kohlendorfer
authors.forename: U
authors.initials: U
authors.lastname: Felderhoff-Mueser
authors.forename: M
authors.initials: M
authors.lastname: Keller
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000188:drug therapy / Q000209:etiology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D045442:Rotarod Performance Test; D013997:Time Factors
chemical_list: D012333:RNA, Messenger; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor