title: 15-Deoxy-Δ12,14-prostaglandin J2induced neurotoxicity via suppressing phosphoinositide 3-kinase.
abstract: 15-Deoxy-Δ12,14-prostaglandin J2(15d-PGJ2) induces neuronal cell death via apoptosis independently of its receptors. 15d-PGJ2inhibits growth factor-induced cell proliferation of primary astrocytes via down-regulating phosphoinositide 3-kinase (PI3K)-Akt pathway. Although 15d-PGJ2-reduced cell viability is accompanied with attenuation of the PI3K signaling in neuroblastoma, it has not been sufficiently clarified how 15d-PGJ2induces cell death in primary neurons. Here, we found that 15d-PGJ2exhibited neurotoxicity via inhibiting the PI3K signaling in the primary culture of rat cortical neurons. A PI3K inhibitor induced neuronal cell death regardless serum throughout maturation, confirming that PI3K is required for neuronal cell survival. The inhibitor disrupted neuronal cell bodies, shortened neurites thinly, damaged plasma membranes and activated caspase-3 similarly to 15d-PGJ2. Little additive or synergistic neurotoxicity was detected between 15d-PGJ2and the PI3K inhibitor. A PI3K activator prevented neurons from undergoing the 15d-PGJ2-induced cell death in vitro. In vivo, the PI3K signaling is required for contextual memory retrieval, which was impaired by bilateral injection of 15d-PGJ2into hippocampus. The activator suppressed the 15d-PGJ2-impaired memory retrieval significantly. In neurons as well as primary astrocytes and neuroblastomas, 15d-PGJ2exhibited cytotoxicity via suppressing the PI3K-Akt pathway in vivo and in vitro.
authors: Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo, 670-8524 Japan.
authors: Hiromi
authors: H
authors: Koma
authors: Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo, 670-8524 Japan.
authors: Yasuhiro
authors: Y
authors: Yamamoto
authors: Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo, 670-8524 Japan.
authors: Ayaka
authors: A
authors: Nishii
authors: Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Hyogo, 670-8524 Japan. Electronic address: yagami@himeji-du.ac.jp.
authors: Tatsurou
authors: T
authors: Yagami
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D007276:Injections, Intraventricular; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011247:Pregnancy; D015230:Prostaglandin D2 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015230:Prostaglandin D2; C097240:15-deoxy-delta(12,14)-prostaglandin J2
keywords: 15-Deoxy-Δ(12,14)–prostaglandin J(2); Cerebral cortex; Hippocampus; Memory retrieval; Neurotoxicity; Phosphoinositide 3-kinase