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

摘要: Increased oxyradical production and membrane lipid peroxidation occur in neurons under physiological conditions neurodegenerative disorders. Lipid can alter synaptic plasticity may increase the vulnerability of to excitotoxicity, but underlying mechanisms are unknown. We report that 4-hydroxy-2,3-nonenal (4HN), an aldehyde product peroxidation, exerts a biphasic effect on NMDA-induced current cultured rat hippocampal with being increased during first 2 h decreased after 6 h. Similarly, 4HN causes early delayed decrease elevation intracellular Ca2+ levels. In contrast, affects neither ion nor response α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA). The initial enhancement is associated phosphorylation NR1 receptor subunit, whereas suppression cellular ATP depletion mitochondrial depolarization. Cell death induced by attenuated NMDA antagonist, not AMPA antagonist. A secreted form amyloid precursor protein, previously shown protect against oxidative excitotoxic insults, prevented each effects including late changes current, depletion, cell death. These findings show modulate channel activity, suggesting role for this pathophysiological responses stress.