title: Prostaglandin E2 rescues cortical neurons from amyloid beta protein-induced apoptosis.
abstract: Cerebrospinal fluid prostaglandin E(2) (PGE(2)) levels are elevated in patients with Alzheimer's disease (AD), suggesting an involvement of PGE(2) in the neurodegeneration. AD is characterized by deposits of amyloid beta protein (Abeta) in various regions of the brain, e.g. the cerebral cortex. In the present study, we investigated the effects of PGE(2) on neuronal survival in primary cultures of rat cortical neurons. PGE(2) had no effect on neuronal cell viability or its morphology. Therefore, we examined the synergistic effects of PGE(2) with Abeta, a neurotoxin. Abeta caused neuronal cell death via apoptosis. PGE(2) significantly suppressed Abeta neurotoxicity, but did not promote the neurotoxicity. Furthermore, PGE(2) ameliorated Abeta-induced apoptotic features such as the condensation of chromatin and the fragmentation of DNA. Abeta increased the influx of Ca(2+) into neurons before cell death. Nimodipine, an inhibitor of the L-type voltage-sensitive calcium channel (L-VSCC), significantly reduced Abeta-potentiated Ca(2+) uptake. On the other hand, there was no effect on the Abeta-induced Ca(2+) influx by an N-VSCC blocker or P/Q-VSCC blockers. Moreover, the inhibitor of L-VSCC suppressed Abeta-induced neuronal cell death, whereas neither an N-VSCC blocker nor P/Q-VSCC blockers affected the neurotoxicity of Abeta. PGE(2) also suppressed the Abeta-induced Ca(2+) influx in a concentration-dependent manner. This study demonstrated that PGE(2) rescues cortical neurons from Abeta-induced apoptosis by reducing Ca(2+) influx in the primary culture. Furthermore, the present study suggested that the inhibition of L-VSCC contributes to the neuroprotective effect of PGE(2).
authors.affiliation: Discovery Research Laboratories, Shionogi and Co, Ltd, 12-4 Sagisu 5-Chome, Fukushima-ku, Osaka 553-0002, Japan. tatsurou.yagami@shionogi.co.jp
authors.forename: Tatsurou
authors.initials: T
authors.lastname: Yagami
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakazato
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ueda
authors.forename: Kenji
authors.initials: K
authors.lastname: Asakura
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kuroda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hata
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaeda
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: Tsuzuki
authors.initials: T
authors.lastname: Hiroshige
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Kambayashi
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D015232:Dinoprostone