Effects of an endothelin B receptor agonist on secretory phospholipase A2-IIA-induced apoptosis in cortical neurons.
Endothelin (ET), a vasoconstrictive peptide, acts as an anti-apoptotic factor, and endothelin receptor B (ETB receptor) is associated with neuronal survival in the brain. Human group IIA secretory phospholipase A2 (sPLA2-IIA) is expressed in the cerebral cortex after brain ischemia and causes neuronal cell death via apoptosis. In primary cultures of rat cortical neurons, we investigated the effects of an ETB receptor agonist, ET-3, on sPLA2-IIA-induced cell death. sPLA2-IIA caused neuronal cell death in a concentration- and time-dependent manner. ET-3 significantly prevented neurons from undergoing sPLA2-IIA-induced cell death. These agonists reversed sPLA2-IIA-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA. Before cell death, sPLA2-IIA potentiated the influx of Ca2+ into neurons. Blockers of the L-type voltage-dependent calcium channel (L-VSCC) not only suppressed the Ca2+ influx, but also exhibited neuroprotective effects. As well as L-VSCC blockers, ET-3 significantly prevented neurons from sPLA2-IIA-induced Ca2+ influx. An ETB receptor antagonist, BQ788, inhibited the effects of ET-3. The present cortical cultures contained few non-neuronal cells, indicating that the ETB receptor agonist affected the survival of neurons directly, but not indirectly via non-neuronal cells. In conclusion, we demonstrate that the ETB receptor agonist rescues cortical neurons from sPLA2-IIA-induced apoptosis. Furthermore, the present study suggests that the inhibition of L-VSCC contributes to the neuroprotective effects of the ETB receptor agonist.
Yagami
Tatsurou
T
Discovery Research Laboratories, Shionogi and Co, Ltd., 12-4 Sagisu 5-Chome, Fukushima-ku, Osaka 553-0002, Japan. yagami@pharmac.med.yokohama-cu.ac.jp
Ueda
Keiichi
K
Sakaeda
Toshiyuki
T
Okamura
Noboru
N
Nakazato
Hitoshi
H
Kuroda
Takayuki
T
Hata
Satoshi
S
Sakaguchi
Gaku
G
Itoh
Naohiro
N
Hashimoto
Yutaka
Y
Fujimoto
Masafumi
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019334:Endothelin-3 / Q000494:pharmacology; D005260:Female; D054501:Group II Phospholipases A2; D006801:Humans; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010741:Phospholipases A / Q000494:pharmacology*; D054467:Phospholipases A2; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B / Q000819:agonists* / Q000502:physiology
D019334:Endothelin-3; D044023:Receptor, Endothelin B; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2