4-Hydroxynonenal, a lipid peroxidation byproduct of spinal cord injury, is cytotoxic for oligodendrocyte progenitors and inhibits their responsiveness to PDGF.
Oligodendroglial reactions to compression injury of spinal cord include apoptosis, secondary demyelination, and remyelination failure. Within hours after contusion, the membrane lipid peroxidation (MLP) byproduct, 4-hydroxynonenal (HNE), increases rapidly in gray matter and thereafter in white matter tracts beyond the initial lesion level. Considering that HNE is a mediator and marker of neuronal MLP toxicity in various neurodegenerative conditions, the present study examined its effect on the regeneration potential of oligodendrocyte progenitors, as defined by their capacity to survive, proliferate 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 tissue undergoing peroxidative injury. In addition, sublethal concentrations of HNE inhibited the mitogenic and chemotactic responses of more immature progenitors to platelet-derived growth factor. These effects appear to be mediated in part by the formation of HNE adducts with progenitor proteins located within the plasma membrane and cytoplasmic compartments. Our data are the first to show that HNE can have direct, deleterious effects on oligodendrocyte precursors. The present study also suggests a mechanism by which the striking accumulation of HNE in white matter tracts surrounding the site of spinal cord compression injury and in other ischemic-hypoxic insults associated with MLP could suppress the potential regenerative response of endogenous oligodendrocyte progenitor cells.
Department of Cell Biology and Neuroscience, 2038 Medical Sciences Building, College of Medicine, University of South Alabama, Mobile, AL 36688-0002, USA. agard@jaguar1.usouthal.edu
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D000447:Aldehydes / Q000633:toxicity*; D000818:Animals; D016923:Cell Death; D002455:Cell Division; D002478:Cells, Cultured; D002633:Chemotaxis / Q000502:physiology; D009836:Oligodendroglia / Q000187:drug effects* / Q000502:physiology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D013234:Stem Cells / Q000187:drug effects* / Q000502:physiology
D000447:Aldehydes; D010982:Platelet-Derived Growth Factor; C027576:4-hydroxy-2-nonenal