Apoptosis and White Matter Injury in Preterm Infants

Abstract

White matter injury in premature infants with or without intraventricular hemorrhage (IVH) remains an important cause of neonatal mortality and neurologic morbidity. The contribution of apoptosis to the cellular death in white matter injury in the preterm infant is unclear. The objective of this study was to determine whether apoptosis contributes to the cellular death in premature infants with cranial ultrasound (US) evidence of IVH and asymmetric periventricular echogenicity (PVE). Brain tissue incorporating frontoparietal white matter was obtained from 21 infants: 6 infants with severe IVH and asymmetric PVE (grade 1V IVH) on US (group 1); 9 infants with minimal IVH or normal US who died within 21 days (group II); and 6 infants with minimal IVH or normal US who died later (group III). The presence of DNA fragmentation, typical of apoptosis, was determined using a terminal deoxytransferase-mediated dUTD nick-end labeling (TUNEL) assay. The TUNEL index for group I infants was significantly greater, i.e., 2.75 +/- 1.94% versus 0.84 +/- 0.70% for group II and 0.42 +/- 0.22 for group III infants (P = 0.004). Most cells showing reactivity had morphologic characteristics consistent with astrocytes and oligodendroglia. The number of white matter cells showing morphologic changes consistent with apoptosis, such as nuclear blebs and karyorrhexis, was also quantitated and was significantly more numerous in group I than in group II infants, i.e., 0.51 +/- 0.64% versus 0.02 +/- 0.05% (P = 0.0005), and group III infants, i.e., 0.10 +/- 0.18% (P = 0.03). These findings implicate apoptosis as a contributing mechanism for the cellular death in infants with IVH and asymmetric PVE. Strategies aimed at preventing the white matter injury will need to incorporate methods of inhibiting the ongoing process of apoptosis.

Astrocyte‐derived glutathione attenuates hemin‐induced apoptosis in cerebral microvascular cells

“…Focal astrocyte loss increased basal microvascular damage and BBB dysfunction (Willis et al, 2004). Astrocytic cell death was also observed within the white matter of preterm infants after an intraventricular hemorrhage (Chamnanvanakij et al, 2002) and loss of astrocytes within the perihematoma region temporally preceded vascular injury after experimental ICH (Gong et al, 2001; Wasserman et al, 2007). These findings raise the unexplored possibility that glial cell loss may remove a key source of protective factors resulting in increased neurovascular damage and a poor clinical outcome after ICH.…”

Endoplasmic Reticulum Stress, Inflammation, and Perinatal Brain Damage

“…TNF-α receptors have been identified in human brains with PVL, raising the possibility that activation of these TNF-α receptors contributes to inflammatory reactions and apoptosis (102). Indeed, apoptosis is prominent in the brains of infants who died with white matter injury (103). Exposing developing oligodendrocytes to TNF increases apoptosis (104) and reduced staining for myelin basic protein (MBP) (105), which might help explain the reduced myelination that is considered a hallmark of inflammation-associated white matter damage in preterm infants (106).…”

Patterns of cerebral white matter damage and cognitive impairment in adolescents born very preterm

“…Several studies suggest that brain damage in preterms predominantly involves white matter (WM) (e.g., Stewart et al, 1999; Hüppi et al, 2001; Counsell et al, 2003; Hüppi, 2004; Gimenez et al, 2006), while others report periventricular (PV) WM damage to be the most common brain abnormality in preterm subjects (Volpe, 1997, 2001; Childs et al, 2001; Miller et al, 2002; Inder et al, 2003). Furthermore, axonal brain connectivity is mainly developed during the preterm period, which is highly vulnerable to cerebral WM damage (e.g., Follett et al, 2000; Back et al, 2001; Chamnanvanakij et al, 2002; McQuillen and Ferriero, 2004).…”