Systemic G-CSF treatment does not improve long-term outcome after neonatal hypoxic-ischemic brain injury

Background: Hypoxia-ischaemia (HI) is a major cause 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 act neuroprotective in rodent models of ischaemic stroke and is currently subject to phase I/II clinical trials in adults. Results on the effect of G-CSF in perinatal brain damage are contradictory. We have previously shown that G-CSF increases NMDAR-mediated excitotoxic brain injury. Aim: We aim to evaluate the long term effect of G-CSF on long term outcome after HI. Methods: On postnatal day 5 (P5) mice pubs were at first randomly assigned to sham operation or HI, second into 4 treatment groups: i) G-CSF ii) phosphate buffered saline (PBS), 1 hour after injury iii) G-CSF iv) PBS, 60 hours after injury. G-CSF (200µg/kg) was administered five times with a 24h interval. Neuromotor and cognitive outcome were assessed by open field, novel object recognition test and RotaRod starting on P90 with subsequent histological analyses of brain injury. Results: G-CSF treatment did neither improve neurobehavioural outcome, nor brain injury. Interestingly the application of PBS and G-CSF in the acute phase after the injury increased brain damage, most pronounced in the hippocampus. Conclusion: We cannot confirm the neuroprotective properties of G-CSF in neonatal HI brain damage. The exacerbation of brain injury by administration of substances in the acute phase indicates that pain and/or stress shortly after injury are important factors contributing to perinatal brain injury.