Selective and biphasic effect of the membrane lipid peroxidation product 4-hydroxy-2,3-nonenal on N-methyl-D-aspartate channels

Increased oxyradical production and membrane lipid peroxidation occur in ne urons under physiological conditions and in neurodegenerative disorders. Li pid peroxidation can alter synaptic plasticity and may increase the vulnera bility of neurons to excitotoxicity, but the underlying mechanisms are unkn own. We report that 4-hydroxy-2,3-nonenal (4HN), an aldehyde product of lip id peroxidation, exerts a biphasic effect on NMDA-induced current in cultur ed rat hippocampal neurons with current being increased during the first 2 h and decreased after 6 h. Similarly, 4HN causes an early increase and a de layed decrease in NMDA-induced elevation of intracellular Ca2+ levels. In c ontrast, 4HN affects neither the ion current nor the Ca2+ response to alpha -amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA). The initial enhanc ement of NMDA-induced current is associated with increased phosphorylation of the NR1 receptor subunit, whereas the delayed suppression of current is associated with cellular ATP depletion and mitochondrial membrane depolariz ation. Cell death induced by 4HN is attenuated by an NMDA receptor antagoni st, but not by an AMPA receptor antagonist. A secreted form of amyloid prec ursor protein, previously shown to protect neurons against oxidative and ex citotoxic insults, prevented each of the effects of 4HN including the early and late changes in NMDA current, delayed ATP depletion, and cell death. T hese findings show that the membrane lipid peroxidation product 4HN can mod ulate NMDA channel activity, suggesting a role for this aldehyde in physiol ogical and pathophysiological responses of neurons to oxidative stress.