title: Midazolam inhibits the hypoxia-induced up-regulation of erythropoietin in the central nervous system.
abstract: Erythropoietin (EPO), a regulator of red blood cell production, is endogenously expressed in the central nervous system. It is mainly produced by astrocytes under hypoxic conditions and has proven to have neuroprotective and neurotrophic effects. In the present study, we investigated the effect of midazolam on EPO expression in primary cultured astrocytes and the mouse brain. Midazolam was administered to 6-week-old BALB/c male mice under hypoxic conditions and pregnant C57BL/6N mice under normoxic conditions. Primary cultured astrocytes were also treated with midazolam under hypoxic conditions. The expression of EPO mRNA in mice brains and cultured astrocytes was studied. In addition, the expression of hypoxia-inducible factor (HIF), known as the main regulator of EPO, was evaluated. Midazolam significantly reduced the hypoxia-induced up-regulation of EPO in BALB/c mice brains and primary cultured astrocytes and suppressed EPO expression in the fetal brain. Midazolam did not affect the total amount of HIF proteins but significantly inhibited the nuclear expression of HIF-1α and HIF-2α proteins. These results demonstrated the suppressive effects of midazolam on the hypoxia-induced up-regulation of EPO both in vivo and in vitro.
authors.affiliation: Department of Anesthesia, Kyoto University Hospital, 54 Kawahara-Cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Matsuyama
authors.affiliation: Department of Anesthesia, Kyoto University Hospital, 54 Kawahara-Cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address: 665tana@kuhp.kyoto-u.ac.jp.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Anesthesia, Kyoto University Hospital, 54 Kawahara-Cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Department of Anesthesia, Kyoto University Hospital, 54 Kawahara-Cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Daijo
authors.affiliation: Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, MA 02114, USA.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kai
authors.affiliation: Department of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Harada
authors.affiliation: Department of Anesthesia, Kyoto University Hospital, 54 Kawahara-Cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005311:Fetal Hypoxia / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D008874:Midazolam / Q000494:pharmacology*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004921:Erythropoietin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008874:Midazolam; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse
keywords: Erythropoietin; Hypoxia-inducible factor; Midazolam