Sara Sanz-Blasco, Maria Calvo-Rodríguez, Erica Caballero, Monica Garcia-Durillo, Lucia Nunez and Carlos Villalobos* Pages 504 - 510 ( 7 )
Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). </P><P> Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. </P><P> Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.
Alzheimer's disease, non-steroidal anti-inflammatory drugs, calcium, mitochondria, amyloid β oligomers, N-methyl-D-aspartate.
Institute of Molecular Biology and Genetics (IBGM), National Research Council of Spain (CSIC), Valladolid, Institute of Molecular Biology and Genetics (IBGM), National Research Council of Spain (CSIC), Valladolid, Institute of Molecular Biology and Genetics (IBGM), National Research Council of Spain (CSIC), Valladolid, Institute of Molecular Biology and Genetics (IBGM), National Research Council of Spain (CSIC), Valladolid, Institute of Molecular Biology and Genetics (IBGM), National Research Council of Spain (CSIC), Valladolid, Institute of Molecular Biology and Genetics (IBGM), National Research Council of Spain (CSIC), Valladolid