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Susceptibility to excitotoxicity in aged hippocampal cultures and neuroprotection by non‐steroidal anti‐inflammatory drugs: role of mitochondrial calcium
Author(s) -
Calvo María,
SanzBlasco Sara,
Caballero Erica,
Villalobos Carlos,
Núñez Lucía
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13004
Subject(s) - excitotoxicity , neuroprotection , nmda receptor , hippocampal formation , pharmacology , neuroscience , glutamate receptor , mitochondrion , biology , chemistry , microbiology and biotechnology , receptor , biochemistry
Brain 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 ( NSAID s) 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 NSAID s. We found that NMDA increased cytosolic Ca 2+ concentration in young, mature and aged neurons but only promoted apoptosis in aged neurons. Resting Ca 2+ 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 Ca 2+ uptake only in aged cultures. Consistently, specific inhibition of mitochondrial Ca 2+ uptake decreased apoptosis. Finally, we found that a series of NSAID s depolarized mitochondria and inhibited mitochondrial Ca 2+ overload, thus preventing NMDA ‐induced apoptosis in aged cultures. We conclude that mitochondrial Ca 2+ uptake is critical for age‐related susceptibility to excitotoxicity and neuroprotection by NSAID s.Rat hippocampal neurons aged in culture were used to investigate mechanisms of age‐related susceptibility to excitotoxicity and neuroprotection by non‐steroidal anti‐inflammatory drugs (NSAIDs). Old neurons display enhanced resting calcium and responses to NMDA along with increased expression of NMDA receptor subunits NR1 and NR2A altogether favoring mitochondrial calcium overload. NSAIDs protect neurons against excitotoxicity acting on mitochondrial calcium uptake. NMDA, N methyl d ‐aspartate.