In vivo assessment of lipid peroxidation products associated with age-related neurodegenerative diseases.

Numerous in vitro and cell culture experiments indicate that oxidative damage decreases astrocyte glutamate transport activity, and it has been proposed that products of lipid peroxidation, particularly 4-hydroxy-2-nonenal, may contribute to neurodegenerative diseases via inhibition of glutamate or glucose transporter activity. We have directly tested the hypothesis that lipid peroxidation products impair glutamate and glucose transport in vivo. Lipid peroxidation products that irreversibly modify protein lysyl residues caused a two- to sixfold elevation in extracellular glutamate in striatum and cerebral cortex of both freely moving and anesthetized rats undergoing microdialysis. No concomitant change in extracellular glucose concentrations was observed. Furthermore, lipid peroxidation product-evoked extracellular glutamate appeared to be derived from nonneuronal sources. Our results demonstrate a biochemical mechanism whereby oxidative damage products can increase extracellular glutamate levels in vivo, providing support for the proposal that oxidative damage leads to inhibition of glutamate transport and thereby may contribute to the progression of neurodegenerative diseases.