4‐Hydroxynonenal, a lipid peroxidation byproduct of spinal cord injury, is cytotoxic for oligodendrocyte progenitors and inhibits their responsiveness to PDGF

Abstract

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.

α‐Phenyl‐n‐tert‐butyl‐nitrone reduces lipopolysaccharide‐induced white matter injury in the neonatal rat brain

“…Nitrotyrosine, a marker of nitrosative stress, was found in O4 cells in the infant brain with PVL (Haynes et al, 2003). HNE and MDA (Christen, 2000), products of lipid peroxidation which are known to be toxic to premyelinating OLs (McCracken et al, 2000;Gard et al, 2001), have also been found in the infant brain with PVL (Haynes et al, 2003). These findings strongly support the link between PVL and ROS or RNS.…”

Involvement of 4-hydroxy-2-nonenal Accumulation in Multiple System Atrophy

“…The representative lipid peroxidation product HNE modifies and crosslinks amino acid residues of α-synuclein to promote molecular aggregation of this protein [28]. HNE also inhibits normal proteasomal and lysosomal functions but not ubiquitination in neurons [4, 5, 15, 17], impairs glutamate and glucose transport in neurons [16, 27], and induces programmed cell death of neurons and oligodendrocytic progenitors [6, 19, 22]; these mechanisms are mediated by HNE-driven oxidative stress. Thus, our results suggest a critical role for HNE, as an α-synuclein-induced lipid peroxidation product, in the processes of neuronal and oligodendroglial degeneration in MSA, including ROS-induced cell damage, inhibition of the proteolytic mechanisms, and formation of the NCIs and GCIs.…”

Interleukin-1β-induced brain injury in the neonatal rat can be ameliorated by α-phenyl-n-tert-butyl-nitrone

“…Nitrotyrosine, a marker of nitrosative stress, was found in O4 cells in the infant brain with PVL (Haynes et al, 2003). HNE and MDA (Christen 2000), products of lipid peroxidation which are known to be toxic to premyelinating OLs (Gard et al, 2001; McCracken et al, 2000), have also been found in the infant brain with PVL (Haynes et al, 2003). These findings strongly support the link between the loss of OLs and ROS or RNS.…”