Non-steroidal anti-inflammatory drugs protect amyloid β protein-induced increase in the intracellular Cl- concentration in cultured rat hippocampal neurons

Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen reportedly decrease a risk for the progression of Alzheimer's disease (AD), whose mechanisms are still controversial. We previously reported that pathophysiological concentrations (1-10 nM) of amyloid p proteins (Aps) increased intracellular Cl- concentration ([Cl-](i)) and aggravated glutamate neurotoxicity in the rat brain neuronal culture. In this study, we examined the effects of therapeutic concentrations of ibuprofen and other drugs with cyclo-oxygenase (COX)-1 and/or COX-2 inhibiting activities on 10 nM Abeta(25-35)-induced changes in cultured rat hippocampal neurons. Ibuprofen (10-100 muM) dose-dependently inhibited the Abeta(25-35)-induced increase in [Cl-](i) in pyramidal cell-like neurons. Not only ibuprofen, aspirin (100 muM), indomethacin (50 muM), and selective COX-1 or COX-2 inhibitor (10 nM ketrolac or 2 muM NS398) also blocked the Abeta-induced increase in neuronal [Cl-](i), though such effects of COX-2 preferring drugs were limited in aggregated Abeta-induced changes. Further, ibuprofen as well as selective COX-1 or COX-2 inhibitor reduced Abeta-induced aggravation of glutamate toxicity as assessed by cell viability. These findings suggest that NSAIDs protect neurons from Abeta-induced degeneration via inhibition of neuronal COX-1 as well as COX-2. (C) 2004 Elsevier Ireland Ltd. All rights reserved.