4-HYDROXYNONENAL, A LIPID-PEROXIDATION PRODUCT, RAPIDLY ACCUMULATES FOLLOWING TRAUMATIC SPINAL-CORD INJURY AND INHIBITS GLUTAMATE UPTAKE

Traumatic injury to the spinal cord initiates a host of pathophysiolog ical events that are secondary to the initial insult. One such event i s the accumulation of free radicals that damage lipids, proteins, and nucleic acids. A major reactive product formed following lipid peroxid ation is the aldehyde, 4-hydroxynonenal (HNE), which cross-links to si de chain amino acids and inhibits the function of several key metaboli c enzymes. In the present study, we used immunocytochemical and immuno blotting techniques to examine the accumulation of protein-bound HNE, and synaptosomal preparations to study the effects of spinal cord inju ry and HNE formation on glutamate uptake. Protein-bound HNE increased in content in the damaged spinal cord at early times following injury (1-24 h) and was found to accumulate in myelinated fibers distant to t he site of injury. Immunoblots revealed that protein-bound HNE levels increased dramatically over the same postinjury interval. Glutamate up take in synaptosomal preparations from injured spinal cords was decrea sed by 65% at 24 h following injury. Treatment of control spinal cord synaptosomes with HNE was found to decrease significantly, in a dose-d ependent fashion, glutamate uptake, an effect that was mimicked by ind ucers of lipid peroxidation. Taken together, these findings demonstrat e that the lipid peroxidation product HNE rapidly accumulates in the s pinal cord following injury and that a major consequence of HNE accumu lation is a decrease in glutamate uptake, which may potentiate neurona l cell dysfunction and death through excitotoxic mechanisms.