Tumour necrosis factor blockade after asphyxia in foetal sheep ameliorates cystic white matter injury.

Cystic white matter injury (WMI) is highly associated with severe neurodevelopmental disability and cerebral palsy in preterm infants, yet its pathogenesis remains poorly understood and there is no established treatment. In the present study we tested the hypothesis that slowly evolving cystic WMI after hypoxia-ischaemia is mediated by programmed necrosis initiated by tumour necrosis factor (TNF). TNF blockade was begun 3 days after hypoxia-ischaemia in order to target the tertiary phase of injury, when the majority of secondary cell death is thought to be complete. Chronically instrumented preterm fetal sheep (0.7 gestation) received 25 minutes of hypoxia-ischaemia induced by complete umbilical cord occlusion (UCO) or sham-UCO (controls, n = 10), followed by intracerebroventricular infusion of the soluble TNF inhibitor, Etanercept, at 3, 8 and 13 days after UCO (UCO-Etanercept, n = 9) or vehicle (UCO-vehicle, n = 9). Fetal brains were processed for histology at 21 days after UCO. UCO-vehicle was associated with a spectrum of macroscopic white matter degeneration, including white matter atrophy, ventriculomegaly and overt temporal lobe cystic WMI. Oligodendrocyte maturational arrest and impaired labelling of myelin proteins, characteristic of diffuse WMI, was observed in the parietal lobe and surrounding the cystic lesions in the temporal lobe. Etanercept markedly attenuated cystic WMI on the side of the intracerebroventricular infusion, with partial contralateral protection. Further, Etanercept improved oligodendrocyte maturation and labelling of myelin proteins in the temporal and parietal lobes. The present study shows that cystic WMI reflects late-onset tertiary cell death mediated by delayed neuroinflammation through the TNF pathway. Delayed TNF blockade markedly attenuated cystic WMI and restored oligodendrocyte maturation and deficits in myelin protein expression. These data suggest that delayed TNF blockade may represent a viable therapeutic strategy to reduce the risk of cystic and diffuse WMI and potentially cerebral palsy after preterm birth, with a surprisingly wide therapeutic window.