4-hydroxynonenal, a lipid peroxidation byproduct of spinal cord injury, iscytotoxic for oligodendrocyte progenitors and inhibits their responsiveness to PDGF

Oligodendroglial reactions to compression injury of spinal cord include apo ptosis, secondary demyelination, and remyelination failure. Within hours af ter contusion, the membrane lipid peroxidation (MLP) byproduct, 4-hydroxyno nenal (HNE), increases rapidly in gray matter and thereafter in white matte r tracts beyond the initial lesion level. Considering that HNE is a mediato r and marker of neuronal MLP toxicity in various neurodegenerative conditio ns, the present study examined its effect on the regeneration potential of oligodendrocyte progenitors, as defined by their capacity to survive, proli ferate and migrate in primary culture. Treatment of oligodendroblasts with HNE evoked a time- and dose-dependent cytotoxicity resembling apoptosis at aldehyde concentrations known to be produced by neurons and achieved in tis sue undergoing peroxidative injury. In addition, sublethal concentrations o f HNE inhibited the mitogenic and chemotactic responses of more immature pr ogenitors to platelet-derived growth factor. These effects appear to be med iated in part by the formation of HNE adducts with progenitor proteins loca ted within the plasma membrane and cytoplasmic compartments. Our data are t he first to show that HNE can have direct, deleterious effects on oligodend rocyte precursors. The present study also suggests a mechanism by which the striking accumulation of HNE in white matter tracts surrounding the site o f spinal cord compression injury and in other ischemic-hypoxic insults asso ciated with MLP could suppress the potential regenerative response of endog enous oligodendrocyte progenitor cells. (C) 2001 Wiley-Liss, Inc.