S-2474, a novel nonsteroidal anti-inflammatory drug, rescues cortical neurons from human group IIA secretory phospholipase A(2)-induced apoptosis.
The elevated level of group IIA secretory phospholipase A(2) (sPLA(2)-IIA) activity contributes to neurodegeneration in the cerebral cortex after ischemia. The up-regulation of cyclooxygenase-2 (COX-2) is also relevant to cerebral ischemia in humans. Studies of ischemia with COX-2 inhibitors suggest a clinical benefit. In the present study, we investigated effects of S-2474 on sPLA(2)-IIA-induced cell death in primary cultures of rat cortical neurons, which was established as an in vitro model of brain ischemia. S-2474 is a novel nonsteroidal anti-inflammatory drug (NSAID), which inhibits COX-2 and contains the di-tert-butylphenol antioxidant moiety. S-2474 significantly prevented neurons from undergoing sPLA(2)-IIA-induced cell death. S-2474 completely ameliorated sPLA(2)-IIA-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA. sPLA(2) also generated neurotoxic prostaglandin D(2) (PGD(2)) and free radicals from neurons before cell death. S-2474 significantly inhibited the sPLA(2)-IIA-induced generation of PGD(2). The present cortical cultures contained few non-neuronal cells, indicating that S-2474 affected neuronal survival directly, but not indirectly via non-neuronal cells. The inhibitory effect of S-2474 on COX-2 might contribute to its neuroprotective effect. In conclusion, S-2474 exhibits neuroprotective effects against sPLA(2)-IIA. Furthermore, the present study suggests that S-2474 may possess therapeutic potential for stroke via ameliorating neurodegeneration.
Yagami
T
T
Discovery Research Laboratories, Shionogi and Co., Ltd., 12-4, Sagisu 5-Choume, Fukushima-ku, Osaka 553-0002, Japan. yagami@pharmac.med.yokohama-cu.ac.jp
Ueda
K
K
Hata
S
S
Kuroda
T
T
Itoh
N
N
Sakaguchi
G
G
Okamura
N
N
Sakaeda
T
T
Fujimoto
M
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002219:Carbamates / Q000494:pharmacology; D002452:Cell Count / Q000379:methods; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D002843:Chromatin / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D054501:Group II Phospholipases A2; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D007212:Indolizines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013778:Tetrazolium Salts; D013844:Thiazoles / Q000494:pharmacology*
C409872:((E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)- 2-ethyl-1,2-isothiazolidine-1,1-dioxide); D000894:Anti-Inflammatory Agents, Non-Steroidal; D002219:Carbamates; D002843:Chromatin; D003499:Cyclic S-Oxides; D007212:Indolizines; D013778:Tetrazolium Salts; D013844:Thiazoles; C119389:indoxam; D010741:Phospholipases A; D054501:Group II Phospholipases A2; C022616:thiazolyl blue