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Lipid peroxidation and the cytotoxic by-product 4-hydroxynonenal (4-HNE) have been implicated in neuronal perikaryal damage. This study sought to determine whether 4-HNE was involved in white matter damage in vivo and in vitro. Immunohistochemical studies detected an increase in cellular and axonal 4-HNE within the ischemic region in the rat after a 24-hour period of permanent middle cerebral artery occlusion. Exogenous 4-HNE (3.2 nmol) was stereotaxically injected into the subcortical white matter of rats that were killed 24 hours later. Damaged axons detected by accumulation of beta-amyloid precursor protein (beta-APP) were observed transversing medially and laterally away from the injection site after intracerebral injection of 4-HNE. In contrast, in the vehicle-treated animals, axonal damage was restricted to an area immediately surrounding the injection site. Exogenous 4-HNE produced oligodendrocyte cell death in culture in a time-dependent and a concentration-dependent manner. After 4 hours, the highest concentration of 4-HNE (50 micromol/L) produced 100% oligodendrocyte cell death. Data indicate that lipid peroxidation and production of 4-HNE occurs in white matter after cerebral ischemia and the lipid peroxidation by-product 4-HNE is toxic to axons and oligodendrocytes.

The neuronal cell adhesion molecule (NCAM) is a key mediator of structural plasticity in the central nervous system, but the mechanisms that control its expression are unknown. Equally, although the transcription factor NF-B is present in the brain, few NF-B-regulated genes relevant for central nervous system function have been identified. We have previously demonstrated that NF-B is activated in neuronal cultures treated with kainic acid or nitric oxide. We show here that kainic acid or nitric oxide also increase the levels of NCAM mRNA and protein in neurons and that this induction of NCAM expression is sensitive to dexamethasone and to antisense, but not missense, oligonucleotides designed to suppress NF-B synthesis. Nitric oxide also stimulates protein binding to an NF-B site in the promoter of the NCAM gene. This indicates that NF-B, which has recently been implicated in synaptic plasticity and also in the etiology of neurodegenerative disease, plays a crucial role in the activity-dependent regulation of NCAM gene expression. In addition, since both NCAM and NF-B are present in the post-synaptic density, this represents a route allowing direct communication between the synapse and the nucleus.In all models of long-lasting synaptic plasticity, the later phases are dependent on the synthesis of new proteins. This may at least partially reflect the requirement for durable structural rearrangement of the synapses. Sprouting of new synaptic contacts is associated with long term facilitation in Aplysia (1), whereas an increase in dendritic spine density (2, 3) or alterations in synaptic clustering (4) or spine architecture (5, 6) are observed in the mammalian hippocampus during long term potentiation (LTP) 1 or memory formation. The effects on the dendritic spine reflect actions either on the spine itself or on the post-synaptic density (psd), a specialized structure within the dendritic spine that receives and transduces the neurotransmitter signals from the presynaptic terminal. Although it is likely that these structural changes are necessary to sustain long term functional plasticity, there are few indications as to the cellular and molecular mechanisms involved. One possibility is that nitric oxide (NO) plays a central role. In many situations, NO release appears to be necessary for the generation of LTP (7-10), whereas recent evidence has suggested that NO can specifically modulate cytoarchitecture (11,12).The psd is composed of a functionally connected network of receptors, channels, enzymes, and scaffolding proteins (13-15). One of the major psd constituents, Ca 2ϩ /calmodulin-dependent protein kinase II (CamKII) (16), is known to play a major role in the induction and maintenance of synaptic plasticity (17)(18)(19)(20)(21)(22). The level of expression of the ␣ subunit of CamKII is increased a few hours after the induction of hippocampal LTP (23, 24), presumably to maintain the heightened sensitivity. We have reported that exposure to NO increases dendritic CamKII␣ mRNA levels (25), an effect likely to be...

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