Nitrosative and Oxidative Injury to Premyelinating Oligodendrocytes in Periventricular Leukomalacia

Abstract

Periventricular leukomalacia (PVL), the major substrate of cerebral palsy in survivors of prematurity, is defined as focal periventricular necrosis and diffuse gliosis in immature cerebral white matter. We propose that nitrosative and/or oxidative stress to premyelinating oligodendrocytes complicating cerebral ischemia in the sick premature infant is a key mechanism of injury interfering with maturation of these cells to myelin-producing oligodendrocytes and subsequent myelination. Using immunocytochemical markers in autopsy brain tissue from 17 PVL cases and 28 non-PVL controls, we found in the PVL cases: 1) selective regionalization of white matter injury, including preferential involvement of the deep compared to intragyral white matter; 2) prominent activation of microglia diffusely throughout the white matter; 3) protein nitration and lipid peroxidation in premyelinating oligodendrocytes in the diffuse component; 4) preferential death of premyelinating oligodendrocytes diffusely; and 5) virtual sparing of the overlying cerebral cortex, as demonstrated by markers of activated astrocytes and microglia. These data establish that PVL is primarily a white matter disease that involves injury to premyelinating oligodendrocytes, potentially through activation of microglia and release of reactive oxygen and nitrogen species. Agents that prevent nitrosative and oxidative stress may play a key role in ameliorating PVL in premature infants in the intensive care nursery.

Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes

“…This conclusion is based on the evidence that (i) removal of NO or superoxide with selective inhibitors͞scavengers abolished LPS-induced death of preOLs; (ii) a specific peroxynitrite decomposition catalyst, FeTMPyP, effectively prevented the cell death; (iii) inhibition of NO production with L-NMMA significantly abolished LPS-initiated oxidation of dichlorohydrofluorescin in microglia, indicating that peroxynitrite was the major oxidant generated by LPS-activated microglia; and (iv) microglia isolated from mice genetically deficient in iNOS or gp91 phox failed to induce preOL death when activated by LPS. Our results are in agreement with recent neuropathological findings that tyrosine nitration, indicative of peroxynitrite formation, is evident in preOLs in the diffuse white matter lesion of PVL (5).…”

“…Thus, the results of this study indicate that activation of microglia may contribute to oligodendroglial damage observed in white matter disorders and provide a mechanistic link between innate immunity and loss of OLs. The data are consistent with recent neuropathological findings showing that the diffuse white matter lesion in PVL is populated with activated microglia (5). Furthermore, other studies demonstrate a positive relationship between maternal-fetal infection, hypoxia͞ ischemia and white matter injury similar to PVL (12)(13)(14).…”

“…Localized activation of microglia, however, has also been implicated in the pathogenesis of a number of neurological diseases and disorders, including ischemia; AIDS-associated dementia (2); chronic neurodegenerative diseases (3), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis; and white matter disorders, such as multiple sclerosis (4) and periventricular leukomalacia (PVL) (5). Microglia are extremely responsive to environmental or immunological challenges and are the predominant cell type producing inflammation-mediated neurodegeneration.…”

α-Phenyl-n-tert-butyl-nitrone attenuates lipopolysaccharide-induced neuronal injury in the neonatal rat brain

“…The LPS-induced cortical neuronal damage observed in the present study might be the result of such a stress. Activated microglia are a major source of reactive oxygen and nitrogen species (Colton and Gilbert, 1993;Chao et al, 1992) and the surrounding area may be affected by the oxidative and nitrosative damage (Haynes et al, 2003(Haynes et al, , 2005Thorburne and Juurlink, 1996). Recent studies have demonstrated the role of NADPH oxidase as a major factor for production of reactive oxygen species in both neurons and glial cells.…”

Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease

“…Overall, the white matter of 7-day pups is more resistant to HI; examination of the 2-day pups 24 h after the HII showed elevated apoptosis of pro-OLs. 78 Similarly, in a study examining autopsied brain tissue from human PVL cases, 79 elevated nitrosative and oxidative damages were seen in pro-OLs.…”