Effect of Gas6 on secretory phospholipase A(2)-IIA-induced apoptosis in cortical neurons.
Gas6, a product of the growth-arrest-specific gene 6, protects cortical neurons from amyloid beta protein (Abeta)-induced apoptosis. Neuronal apoptosis is also caused by human group IIA secretory phospholipase A(2) (sPLA(2)-IIA), which is expressed in the cerebral cortex after brain ischemia. sPLA(2)-IIA induces Ca(2+) influx via L-type voltage-sensitive calcium channels (L-VSCCs), leading to its neurotoxicity. In the present study, we investigated effects of Gas6 on sPLA(2)-IIA-induced cell death in primary cultures of rat cortical neurons. sPLA(2)-IIA caused neuronal cell death in a concentration- and time-dependent manner. Gas6 significantly prevented neurons from sPLA(2)-IIA-induced cell death. Gas6 suppressed sPLA(2)-IIA-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA. Prior to cell death, sPLA(2)-IIA increased the influx of Ca(2+) into neurons through L-VSCCs. Gas6 significantly inhibited the sPLA(2)-IIA-induced Ca(2+) influx. The blocker of L-VSCCs also suppressed sPLA(2)-IIA-induced neuronal cell death. The cortical cultures contained few non-neuronal cells, indicating that Gas6 affected the survival of neurons directly, but not indirectly via non-neuronal cells. In conclusion, we demonstrate that Gas6 rescues cortical neurons from sPLA(2)-IIA-induced apoptosis. Furthermore, the present study indicates that inhibition of L-VSCC contributes to the neuroprotective effect of Gas6.
Yagami
Tatsurou
T
Discovery Research Laboratories, Shionogi and Co. Ltd., 12-4 Sagisu 5-Chome, Fukushima-ku, Osaka 553-0002, Japan. vzx00556@nifty.com
Ueda
Keiichi
K
Asakura
Kenji
K
Okamura
Noboru
N
Sakaeda
Toshiyuki
T
Sakaguchi
Gaku
G
Itoh
Naohiro
N
Hashimoto
Yutaka
Y
Nakano
Toru
T
Fujimoto
Masafumi
M
D000818:Animals; D017209:Apoptosis; D001562:Benzimidazoles / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002452:Cell Count; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005260:Female; D054501:Group II Phospholipases A2; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D010741:Phospholipases A / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D000099255:Growth Arrest-Specific Protein 6
D001562:Benzimidazoles; D002118:Calcium; D002121:Calcium Channel Blockers; D054501:Group II Phospholipases A2; D036341:Intercellular Signaling Peptides and Proteins; D010741:Phospholipases A; D013778:Tetrazolium Salts; D013844:Thiazoles; D000099255:Growth Arrest-Specific Protein 6; C447680:hoechst 32258; C022616:thiazolyl blue