Non-steroidal anti-inflammatory drugs protect amyloid beta 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 beta proteins (Abetas) 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 Abeta25-35-induced changes in cultured rat hippocampal neurons. Ibuprofen (10-100 microM) dose-dependently inhibited the Abeta25-35-induced increase in [Cl-]i in pyramidal cell-like neurons. Not only ibuprofen, aspirin (100 microM), indomethacin (50 microM), and selective COX-1 or COX-2 inhibitor (10 nM ketrolac or 2 microM 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.
Department of Pharmacology, Kansai Medical University, Fumizono-cho 10-15, Moriguchi, Osaka 570-8506, Japan.
Ryoichi
R
Iwata
Kaori
K
Kitagawa
Nan-Yan
NY
Zhang
Bo
B
Wu
Chiyoko
C
Inagaki
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D020128:Inhibitory Concentration 50; D042541:Intracellular Space / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D011806:Quinolinium Compounds; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002712:Chlorides; D016861:Cyclooxygenase Inhibitors; D011806:Quinolinium Compounds; C439320:amyloid beta-protein (25-36); C085493:N-(ethoxycarbonylmethyl)-6-methoxyquinolinium; D018698:Glutamic Acid