The lipid peroxidation by-product 4-hydroxynonenal is toxic to axons and oligodendrocytes

Lipid peroxidation and the cytotoxic by-product 4-hydroxynonenal (4-HNE) ha ve been implicated in neuronal perikaryal damage. This study sought to dete rmine whether 4-HNE was involved in white matter damage in vivo and in vitr o. Immunohistochemical studies detected an increase in cellular and axonal 4-HNE within the ischemic region in the rat after a 24-hour period of perma nent middle cerebral artery occlusion. Exogenous 4-HNE (3.2 nmol) was stere otaxically injected into the subcortical white matter of rats that were kil led 24 hours later. Damaged axons detected by accumulation of beta -amyloid precursor protein (beta -APP) were observed transversing medially and late rally away from the injection site after intracerebral injection of 4-HNE. In contrast, in the vehicle-treated animals, axonal damage was restricted t o an area immediately surrounding the injection site. Exogenous 4-HNE produ ced oligodendrocyte cell death in culture in a time-dependent and a concent ration-dependent manner. After 4 hours, the highest concentration of 4-HNE (50 mu mol/L) produced 100% oligodendrocyte cell death. Data indicate that lipid peroxidation and production of 4-HNE occurs in white matter after cer ebral ischemia and the lipid peroxidation by-product 4-HNE is toxic to axon s and oligodendrocytes.