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Biochem Biophys Res Commun. 2015 Feb 20;457(4):547-53. doi: 10.1016/j.bbrc.2015.01.022. Epub 2015 Jan 16.

Midazolam inhibits the formation of amyloid fibrils and GM1 ganglioside-rich microdomains in presynaptic membranes through the gamma-aminobutyric acid A receptor.

Author information

1
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.
2
Department of Anesthesiology and Medical Crisis Management, Nagoya City University Graduate School of Medical Sciences, Nagoya City, Aichi, Japan.
3
Laboratory of Molecular Medicinal Science, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan.

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.

KEYWORDS:

Alzheimer's disease; Amyloid β-protein; GM1 ganglioside; Midazolam

PMID:
25600806
DOI:
10.1016/j.bbrc.2015.01.022
[Indexed for MEDLINE]

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