title: Endothelial microsomal prostaglandin E synthase-1 facilitates neurotoxicity by elevating astrocytic Ca2+ levels.
abstract: Recurrent seizures may cause neuronal damage in the hippocampus. As neurons form intimate interactions with astrocytes via glutamate, this neuron-glia circuit may play a pivotal role in neuronal excitotoxicity following such seizures. On the other hand, astrocytes contact vascular endothelia with their endfeet. Recently, we found kainic acid (KA) administration induced microsomal prostaglandin E synthase-1 (mPGES-1) and prostaglandin E(2) (PGE(2)) receptor EP3 in venous endothelia and on astrocytes, respectively. In addition, mice deficient in mPGES-1 exhibited an improvement in KA-induced neuronal loss, suggesting that endothelial PGE(2) might modulate neuronal damage via astrocytes. In this study, we therefore investigated whether the functional associations between endothelia and astrocytes via endothelial mPGES-1 lead to neuronal injury using primary cultures of hippocampal slices. We first confirmed the delayed induction of endothelial mPGES-1 in the wild-type (WT) slices after KA-treatment. Next, we examined the effects of endothelial mPGES-1 on Ca(2+) levels in astrocytes, subsequent glutamate release and neuronal injury using cultured slices prepared from WT and mPGES-1 knockout mice. Moreover, we investigated which EP receptor on astrocytes was activated by PGE(2). We found that endothelial mPGES-1 produced PGE(2) that enhanced astrocytic Ca(2+) levels via EP3 receptors and increased Ca(2+)-dependent glutamate release, aggravating neuronal injury. This novel endothelium-astrocyte-neuron signaling pathway may be crucial for neuronal damage after repetitive seizures, and hence could be a new target for drug development.
authors.affiliation: Medical Research Institute, Tokyo Women's Medical University, Shinjuku, Tokyo, Japan. takakot@lab.twmu.ac.jp
authors.forename: Takako
authors.initials: T
authors.lastname: Takemiya
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Matsumura
authors.forename: Hiroko
authors.initials: H
authors.lastname: Sugiura
authors.forename: Shin
authors.initials: S
authors.lastname: Yasuda
authors.forename: Satoshi
authors.initials: S
authors.lastname: Uematsu
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Kanato
authors.initials: K
authors.lastname: Yamagata
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D015232:Dinoprostone / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000201:enzymology*; D018698:Glutamic Acid / Q000378:metabolism; D007124:Immunoenzyme Techniques; D007150:Immunohistochemistry; D019746:Intramolecular Oxidoreductases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000071876:Prostaglandin-E Synthases
chemical_list: D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone; D002118:Calcium