title: Effects of an endothelin B receptor agonist on secretory phospholipase A2-IIA-induced apoptosis in cortical neurons.
abstract: 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.
authors.affiliation: 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
authors.forename: Tatsurou
authors.initials: T
authors.lastname: Yagami
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ueda
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
authors.forename: Noboru
authors.initials: N
authors.lastname: Okamura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakazato
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kuroda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hata
authors.forename: Gaku
authors.initials: G
authors.lastname: Sakaguchi
authors.forename: Naohiro
authors.initials: N
authors.lastname: Itoh
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Masafumi
authors.initials: M
authors.lastname: Fujimoto
mesh_terms: 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
chemical_list: D019334:Endothelin-3; D044023:Receptor, Endothelin B; D010741:Phospholipases A; D054501:Group II Phospholipases A2; D054467:Phospholipases A2