White matter protection with insulin-like growth factor-1 after hypoxia-ischaemia in preterm foetal sheep

Perinatal hypoxia-ischaemia in extremely preterm infants is associated with long-term neurodevelopmental impairment, for which there is no specific treatment. Insulin-like growth factor-1 can reduce acute brain injury, but its effects on chronic white matter injury after hypoxia-ischaemia are unclear. Preterm-equivalent foetal sheep (0.6 gestation) received either sham-asphyxia or asphyxia induced by umbilical cord occlusion for 30 min, and recovered for either 3 or 35 days after asphyxia. The 35 day recovery groups received either an intracerebroventricular infusion of insulin-like growth factor-1 (1 µg/24 h) or vehicle, from 3 to 14 days after asphyxia. Asphyxia was associated with ventricular enlargement, and loss of frontal and parietal white matter area (P < 0.05 versus sham-asphyxia). This was associated with reduced area fraction of myelin basic protein and numbers of oligodendrocyte transcription factor 2 and mature, anti-adenomatous polyposis coli-positive oligodendrocytes in periventricular white matter (P < 0.05), with persistent inflammation and caspase-3 activation (P < 0.05). Four of eight foetuses developed cystic lesions in temporal white matter. Prolonged infusion with insulin-like growth factor-1 restored frontal white matter area, improved numbers of oligodendrocyte transcription factor 2-positive and mature, anti-adenomatous polyposis coli-positive oligodendrocytes, with reduced astrogliosis and microgliosis after 35 days recovery (P < 0.05 versus asphyxia). One of four foetuses developed temporal cystic lesions. Functionally, insulin-like growth factor-1-treated foetuses had faster recovery of EEG power, but not spectral edge. Encouragingly, these findings show that delayed, prolonged, insulin-like growth factor-1 treatment can improve functional maturation of periventricular white matter after severe asphyxia in the very immature brain, at least in part by suppressing chronic neural inflammation.