title: 4-hydroxy-2(E)-Nonenal facilitates NMDA-Induced Neurotoxicity via Triggering Mitochondrial Permeability Transition Pore Opening and Mitochondrial Calcium Overload.
abstract: N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity is one of the major causes for neuronal cell death during cerebral ischemic insult. Previously, we reported that the final product of lipid membrane peroxidation 4-hydroxy-2E-nonenal (HNE) synergistically increased NMDA receptor-mediated excitotoxicity (J Neurochem., 2006). In this study, we investigated the mechanism involved in the synergistic neuronal cell death induced by co-treatment with HNE and NMDA. Although neither HNE (1 µM) nor NMDA (2 µM) alone induced the death of cortical neurons, simultaneous treatment of neuronal cells with HNE and NMDA synergistically evoked the death of the cells. However, the synergistic effect on neuronal death was observed only in the presence of calcium. HNE neither increased the cytosolic calcium level ([Ca(2+)]i) nor altered the NMDA-induced intracellular calcium influx. However, HNE together with NMDA elevated the mitochondrial calcium level and depolarized the mitochondrial transmembrane potential. Furthermore, HNE evoked damage of isolated mitochondria at the cytosolic calcium level (200 nM), which is maximally induced by 2 µM NMDA. Consistently, ATP was depleted in neurons when treated with both HNE and NMDA together. Ciclopirox, a potent inhibitor of mitochondrial permeability transition pore opening (Br. J. Pharmacol., 2005), largely prevented the synergistic damage of mitochondria and death of cortical neurons. Therefore, although low concentrations of HNE and NMDA cannot individually induce neuronal cell death, they can evoke the neuronal cell death by synergistically accelerating mitochondrial dysfunction.
authors.affiliation: Department of Neuroscience, College of Medicine, Korea University, Seoul 136-705, Korea.
authors.forename: In-Young
authors.initials: IY
authors.lastname: Choi
authors.forename: Ji-Hyae
authors.initials: JH
authors.lastname: Lim
authors.forename: Chunsook
authors.initials: C
authors.lastname: Kim
authors.forename: Hwa Young
authors.initials: HY
authors.lastname: Song
authors.forename: Chung
authors.initials: C
authors.lastname: Ju
authors.forename: Won-Ki
authors.initials: WK
authors.lastname: Kim
keywords: 4-hydroxy-2(E)-nonenal (HNE); NMDA; calcium; mitochondria; neuronal death