title: Midazolam inhibits the formation of amyloid fibrils and GM1 ganglioside-rich microdomains in presynaptic membranes through the gamma-aminobutyric acid A receptor.
abstract: Recent studies have suggested that a positive correlation exists between surgical interventions performed under general anesthesia and the risk of developing Alzheimer's disease (AD) in the late postoperative period. It has been reported that amyloid β-protein (Αβ) fibrillogenesis, which is closely related to AD, is accelerated by exposure to anesthetics. However, the mechanisms underlying these effects remain uncertain. This study was designed to investigate whether the anesthetic midazolam affects Αβ fibrillogenesis, and if so, whether it acts through GM1 ganglioside (GM1) on the neuronal surface. Midazolam treatment decreased GM1 expression in the detergent-resistant membrane microdomains of neurons, and these effects were regulated by the gamma-aminobutyric acid-A receptor. Midazolam inhibited Αβ fibril formation from soluble Αβ on the neuronal surface. In addition, midazolam suppressed GM1-induced fibril formation in a cell-free system. Moreover, midazolam inhibited the formation of Αβ assemblies in synaptosomes isolated from aged mouse brains. These finding suggested that midazolam has direct and indirect inhibitory effects on Αβ fibrillogenesis.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Ishikawa, Japan; Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan. Electronic address: na-yamam@hokuriku-u.ac.jp.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Anesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences, Nagoya City, Aichi, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Arima
authors.affiliation: Department of Anesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences, Nagoya City, Aichi, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugiura
authors.affiliation: Department of Anesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences, Nagoya City, Aichi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirate
authors.affiliation: Department of Anesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences, Nagoya City, Aichi, Japan.
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Kusama
authors.affiliation: Laboratory of Molecular Medicinal Science, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Anesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences, Nagoya City, Aichi, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Sobue
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism*; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D005677:G(M1) Ganglioside / Q000378:metabolism*; D008297:Male; D051379:Mice; D008874:Midazolam / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D018079:Receptors, GABA / Q000378:metabolism*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000682:Amyloid; D018686:Anesthetics, Intravenous; D020011:Protective Agents; D018079:Receptors, GABA; D005677:G(M1) Ganglioside; D008874:Midazolam
keywords: Alzheimer's disease; Amyloid β-protein; GM1 ganglioside; Midazolam