title: Na(+), K(+)-ATPase dysfunction causes cerebrovascular endothelial cell degeneration in rat prefrontal cortex slice cultures.
abstract: Cerebrovascular endothelial cell dysfunction resulting in imbalance of cerebral blood flow contributes to the onset of psychiatric disorders such as depression, schizophrenia and bipolar disorder. Although decrease in Na(+), K(+)-ATPase activity has been reported in the patients with schizophrenia and bipolar disorder, the contribution of Na(+), K(+)-ATPase to endothelial cell dysfunction remains poorly understood. Here, by using rat neonatal prefrontal cortex slice cultures, we demonstrated that pharmacological inhibition of Na(+), K(+)-ATPase by ouabain induced endothelial cell injury. Treatment with ouabain significantly decreased immunoreactive area of rat endothelial cell antigen-1 (RECA-1), a marker of endothelial cells, in a time-dependent manner. Ouabain also decreased Bcl-2/Bax ratio and phosphorylation level of glycogen synthase kinase 3β (GSK3β) (Ser9), which were prevented by lithium carbonate. On the other hand, ouabain-induced endothelial cell injury was exacerbated by concomitant treatment with LY294002, an inhibitor of phosphoinositide 3- (PI3-) kinase. We also found that xestospongin C, an inhibitor of inositol triphosphate (IP3) receptor, but not SEA0400, an inhibitor of Na(+), Ca(2+) exchanger (NCX), protected endothelial cells from cytotoxicity of ouabain. These results suggest that cerebrovascular endothelial cell degeneration induced by Na(+), K(+)-ATPase inhibition resulting in Ca(2+) release from endoplasmic reticulum (ER) and activation of GSK3β signaling underlies pathogenesis of these psychiatric disorders.
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kurauchi
authors.affiliation: Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto 860-8555, Japan; Program for Leading Graduate Schools "HIGO (Health Life Science: Interdisciplinary and Glocal Oriented) Program", Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Hisatsune
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.affiliation: Department of Chemico-Pharmacological Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan. Electronic address: hkatsuki@gpo.kumamoto-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katsuki
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020013:Calcium Signaling; D002470:Cell Survival / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017397:Prefrontal Cortex / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046509:Tissue Culture Techniques
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008094:Lithium; D010042:Ouabain; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000254:Sodium-Potassium-Exchanging ATPase
keywords: Cerebrovascular endothelial cell; GSK3β; Na(+), K(+)-ATPase; Ouabain; Pericytes; Prefrontal cortex slice culture