Effects of S‐2474, a novel nonsteroidal anti‐inflammatory drug, on amyloid β protein‐induced neuronal cell death

The accumulation of amyloid β protein (Aβ) in the brain is a characteristic feature of Alzheimer's disease (AD). Clinical trials of AD patients with nonsteroidal anti‐inflammatory drugs (NSAIDs) indicate a clinical benefit. NSAIDs are presumed to act by suppressing inhibiting chronic inflammation in the brain of AD patients. In the present study, we investigated effects of S‐2474 on Aβ‐induced 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 ‐butylphenol antioxidant moiety. S‐2474 significantly prevented neurons from Aβ(25 – 35)‐ and Aβ(1 – 40)‐induced cell death. S‐2474 ameliorated Aβ‐induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA completely. Prior to cell death, Aβ(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. S‐2474 significantly inhibited the Aβ(25 – 35)‐induced generation of PGD 2 and free radicals. The present cortical cultures contained little non‐neuronal cells, indicating that S‐2474 affected neuronal survival directly, but not indirectly via non‐neuronal cells. Both an inhibitory effect of COX‐2 and an antioxidant effect might contribute to the neuroprotective effects of S‐2474. In conclusion, S‐2474 exhibits protective effects against neurotoxicity of Aβ. Furthermore, the present study suggests that S‐2474 may possess therapeutic potential for AD via ameliorating degeneration in neurons as well as suppressing chronic inflammation in non‐neuronal cells.British Journal of Pharmacology (2001) 134 , 673–681; doi: 10.1038/sj.bjp.0704261