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Published on: July 27, 2014
Systemic G-CSF treatment does not improve long-term outcomes after neonatal hypoxic-ischaemic brain injury
G W Schlager1, E Griesmaier, K Wegleiter
1Department of Paediatrics I, University Hospital Essen, Germany.
Insights
Granulocyte colony-stimulating factor (G-CSF) did not improve outcomes in neonatal hypoxia-ischaemia brain injury. Acute G-CSF administration exacerbated brain damage, suggesting it is not neuroprotective in this context.
Area of Science:
- Neuroscience
- Developmental Biology
- Neonatal Medicine
Background:
- Hypoxia-ischaemia (HI) causes significant developmental brain injury in preterm infants.
- Granulocyte colony-stimulating factor (G-CSF) shows mixed results for neuroprotection in neonatal brain damage.
- Previous studies indicated G-CSF may worsen excitotoxic brain injury.
Purpose of the Study:
- To evaluate the long-term neuroprotective effects of G-CSF in a neonatal mouse model of HI.
- To assess G-CSF's impact on neuromotor and cognitive functions post-HI.
- To determine if G-CSF administration influences histological brain injury outcomes.
Main Methods:
- Neonatal mice (postnatal day 5) underwent sham operation or HI.
- Mice were treated with G-CSF or phosphate-buffered saline (PBS) at acute or delayed time points.
- Neuromotor and cognitive functions were assessed at postnatal day 90; histological analyses followed.
Main Results:
- G-CSF treatment did not improve neurobehavioural outcomes or reduce brain injury.
- Acute administration of both PBS and G-CSF increased hippocampal brain damage.
- The study failed to confirm G-CSF's neuroprotective properties in neonatal HI.
Conclusions:
- G-CSF is not neuroprotective against neonatal hypoxia-ischaemia brain injury.
- Acute treatment protocols may exacerbate injury due to heightened neurological sensitivity.
- Further research is needed to understand factors influencing treatment efficacy in acute 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."
