Effects of S-2474, a novel nonsteroidal anti-inflammatory drug, on amyloidbeta protein-induced neuronal cell death

1 The accumulation of amyloid beta protein (A beta) in the brain is a chara cteristic feature of Alzheimer's disease (AD). Clinical trials of AD patien ts with nonsteroidal anti-inflammatory drugs (NSAIDs) indicate a clinical b enefit. NSAIDs are presumed to act by suppressing inhibiting chronic inflam mation in the brain of AD patients. 2 In the present study, we investigated effects of S-2474 on A beta -induce d cell death in primary cultures of rat cortical neurons. S-2474 is a novel NSAID, which inhibits cyclo-oxygenase-2 (COX-2) and contains the di-tert-b utylphenol antioxidant moiety. 3 S-2474 significantly prevented neurons from A beta (25-35)- and A beta (1 -40)-induced cell death. S-2474 ameliorated A beta -induced apoptotic featu res such as the condensation of chromatin and the fragmentation of DNA comp letely. 4 Prior to cell death, A beta (25-35) generated prostaglandin D-2 (PGD(2)) and free radicals from neurons. PGD(2) is a product of cyclo-oxygenase (COX ), and caused neuronal cell death. 5 S-2474 significantly inhibited the A beta (25-35)-induced generation of P GD(2) and free radicals. 6 The present cortical cultures contained little non-neuronal cells, indica ting that S-2474 affected neuronal survival directly, but not indirectly vi a non-neuronal cells. Both an inhibitory effect of COX-2 and an antioxidant effect might contribute to the neuroprotective effects of S-2474. 7 In conclusion, S-2474 exhibits protective effects against neurotoxicity o f A beta. Furthermore, the present study suggests that S-2474 may possess t herapeutic potential for AD via ameliorating degeneration in neurons as wel l as suppressing chronic inflammation in non-neuronal cells.