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Título

Susceptibility to excitotoxicity in aged hippocampal cultures and neuroprotection by non-steroidal anti-inflammatory drugs: role of mitochondrial calcium

AutorCalvo-Rodríguez, María; Sanz-Blasco, Sara; Caballero, Erica ; Villalobos, Carlos ; Núñez, Lucía
Palabras claveHippocampal neurons
Calcium
Mitochondria
NMDA
NSAIDs
Aging
Fecha de publicación2015
EditorInternational Society for Neurochemistry
Blackwell Publishing
CitaciónJournal of Neurochemistry 132(4): 403-417 (2015)
ResumenBrain damage after insult and cognitive decline are related to excitotoxicity and strongly influenced by aging, yet mechanisms of aging-dependent susceptibility to excitotoxicity are poorly known. Several non-steroidal anti-inflammatory drugs (NSAIDs) may prevent excitotoxicity and cognitive decline in the elderly by an unknown mechanism. Interestingly, after several weeks in vitro, hippocampal neurons display important hallmarks of neuronal aging in vivo. Accordingly, rat hippocampal neurons cultured for several weeks were used to investigate mechanisms of aging-related susceptibility to excitotoxicity and neuroprotection by NSAIDs. We found that NMDA increased cytosolic Ca2+ concentration in young, mature and aged neurons but only promoted apoptosis in aged neurons. Resting Ca2+ levels and responses to NMDA increased with time in culture which correlated with changes in expression of NMDA receptor subunits. In addition, NMDA promoted mitochondrial Ca2+ uptake only in aged cultures. Consistently, specific inhibition of mitochondrial Ca2+ uptake decreased apoptosis. Finally, we found that a series of NSAIDs depolarized mitochondria and inhibited mitochondrial Ca2+ overload, thus preventing NMDA-induced apoptosis in aged cultures. We conclude that mitochondrial Ca2+ uptake is critical for age-related susceptibility to excitotoxicity and neuroprotection by NSAIDs.
URIhttp://hdl.handle.net/10261/117008
DOI10.1111/jnc.13004
Identificadoresdoi: 10.1111/jnc.13004
issn: 0022-3042
e-issn: 1471-4159
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