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

Abstract

1. The accumulation of amyloid beta protein (Abeta) 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. 2. In the present study, we investigated effects of S-2474 on Abeta-induced cell death in primary cultures of rat cortical neurons. 3. 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 Abeta(25 - 35)- and Abeta(1 - 40)-induced cell death. S-2474 ameliorated Abeta-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA completely. 4. Prior to cell death, Abeta(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 Abeta(25 - 35)-induced generation of PGD(2) and free radicals. 6. 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. 7. In conclusion, S-2474 exhibits protective effects against neurotoxicity of Abeta. 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.

• Authors: T Yagami, K Ueda, K Asakura, T Sakaeda, T Kuroda, S Hata, Y Kambayashi, M Fujimoto
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 134 Issue 3 Pg. 673-81 (Oct 2001) ISSN: 0007-1188 [Print] England
• PMID: 11588123 (Publication Type: Journal Article)

Chemical References

• ((E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)- 2-ethyl-1,2-isothiazolidine-1,1-dioxide)
• Amyloid beta-Peptides
• Anti-Inflammatory Agents, Non-Steroidal
• Cyclic S-Oxides
• Thiazoles

Topics

• Amyloid beta-Peptides (pharmacology)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Cell Death (drug effects)
• Cells, Cultured
• Cerebral Cortex (drug effects, pathology)
• Cyclic S-Oxides (pharmacology)
• Dose-Response Relationship, Drug
• Embryo, Mammalian
• Female
• Neurons (drug effects, pathology)
• Pregnancy
• Rats
• Rats, Sprague-Dawley
• Thiazoles (pharmacology)