Haematopoietic growth factors in neonatal brain injury: Effect of G-CSF, SCF and FL on excitotoxic brain injury, short and long-term outcome

Aims: We have shown before that stem cell factor (SCF) and granulocyte-colony stimulating factor (GCSF) alone or in combination increase excitotoxic brain injury and developmental apoptosis when given in the acute phase of brain damage in contrast to results obtained in adult animals. Hypothesis: Since this effect was attributed to proinflammatory stimuli of the cytokines during the acute phase of brain injury, we hypothesized that the delayed administration of either GCSF/SCF or flt3-ligand (FL), another haematopoietic growth factor known to stimulate stem cell release, reduces excitotoxic injury. In addition we evaluated, whether GCSF/SCF and FL treatment in the neonatal period alters the neurobehavioral outcome in adulthood. Methods: In this excitotoxic brain injury model we injected 10µg ibotenic acid, a glutamate-analogue, into the right hemisphere (intracranially) of five day (P5) old mice. Another group of animals was kept without any brain damage (healthy controls). 60 hours later i) GCSF/SCF (GSCF 200µg/kg, SCF 50µg/kg), ii) FL (FL 100µg/kg) or iii) vehicle were randomly injected intraperitoneally every 24 hours for three respectively five days. Endpoints (lesion size, apoptosis; Rotarod test, open field and novel object recognition (only at P90)) were determined at P10, P18 and P90. Results: Delayed administration of GCSF/SCF and FL significantly reduced excitotoxic brain injury at all three time endpoints, the number of apoptotic cells was not affected neither in the area of the insult nor in the left undamaged hemisphere. Long-term neurobehavioral outcome was unchanged by these treatments. Conclusion: Our results suggest neuroprotective and neuroregenerative effects of GCSF/SCF and FL on moderate brain injury without major side effects on the developing brain.