Abstract
BackgroundSystemic inflammation is an important risk factor for neurodevelopmental impairments in preterm infants. Premyelinating oligodendrocytes are main building blocks of white matter in preterm infants and vulnerable to oxidative stress and excitotoxic stress. Tumour necrosis factor-α (TNF-α) plays important roles in systemic inflammation and local inflammation leading to apoptosis of premyelinating oligodendrocytes and white matter injury (WMI) in brain tissue. This study was conducted to investigate whether etanercept, a TNF-α antagonist, could attenuate systemic lipopolysaccharide (LPS)-induced WMI in the immature brain.ResultsWe found that intraperitoneal LPS administration caused systemic and local inflammation in brain tissue. Subsequent etanercept treatment significantly attenuated LPS-induced inflammation in brain tissue as well as in systemic circulation. Intraperitoneal LPS also induced microgliosis and astrocytosis in the cingulum and etanercept treatment reduced LPS-induced microgliosis and astrocytosis. Additionally, systemic LPS-induced apoptosis of oligodendrocyte precursor cells was observed, which was lessened by etanercept treatment. The concentration of etanercept in the CSF was higher when it was administrated with LPS than when administrated with a vehicle.ConclusionsIt appears that etanercept reduce WMI in the neonatal rat brain via attenuation of systemic and local inflammation. This study provides preclinical data suggesting etanercept-mediated modulation of inflammation as a promising approach to reduce WMI caused by sepsis or necrotizing enterocolitis in preterm infants.
Highlights
Systemic inflammation is an important risk factor for neurodevelopmental impairments in preterm infants
During the neonatal period, preterm infants are at risk from several morbidities, such as sepsis and necrotizing enterocolitis, that are associated with neurodevelopment impairments [1, 2], which have been shown to be mediated by white matter injury (WMI) in the premature brain [2, 3]
The pathogenesis of WMI is characterised by a loss of premyelinating oligodendrocytes, which are vulnerable to oxidative and excitotoxic stress, and activation of glial cells, such as microglia and astrocytes [4, 5]
Summary
Systemic inflammation is an important risk factor for neurodevelopmental impairments in preterm infants. Premyelinating oligodendrocytes are main building blocks of white matter in preterm infants and vulnerable to oxidative stress and excitotoxic stress. Tumour necrosis factor-α (TNF-α) plays important roles in systemic inflamma‐ tion and local inflammation leading to apoptosis of premyelinating oligodendrocytes and white matter injury (WMI) in brain tissue. The pathogenesis of WMI is characterised by a loss of premyelinating oligodendrocytes (pre-OLs), which are vulnerable to oxidative and excitotoxic stress, and activation of glial cells, such as microglia and astrocytes [4, 5]. Most of studies which reported roll of glial cells and TNF-α in the death of oligodendrocytes during the early developmental phase used in vitro methods with direct stimulation with LPS [8, 10, 11].
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