title: Ketamine reduces amyloid β-protein degradation by suppressing neprilysin expression in primary cultured astrocytes.
abstract: Pathological accumulation of cortical amyloid β-protein (Aβ) is an early and consistent feature of Alzheimer's disease (AD). Aβ levels in the brain are determined by production and catabolism. Previous studies have suggested that deficits in the brain expression of neprilysin (NEP) and the insulin-degrading enzyme (IDE), which are both proteases involved in amyloid degradation, may promote Aβ deposition in patients with sporadic late-onset AD. Because the incidence of AD increases after surgical intervention, we examined whether ketamine, which is a general anaesthetic with neuroprotective properties for excitotoxic ischaemic damage, is associated with Aβ degradation by inducing NEP and IDE expression. The non-competitive N-methyl-d-aspartate receptor antagonist ketamine and MK801 significantly decreased the expression of NEP, but not IDE, in a concentration- and time-dependent manner through the dephosphorylation of p38 mitogen-activated protein kinase (MAPK) in cultured rat astrocytes. Furthermore, NEP-reduced reagents significantly suppressed the degradation of exogenous Aβ in cultured astrocytes. These results suggested that ketamine suppresses the Aβ degradation of NEP by reducing p38 MAPK-mediated pathway activity.
authors.affiliation: Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan. naokisan@ph.ritsumeikan.ac.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Hajime
authors.initials: H
authors.lastname: Arima
authors.forename: Kaori
authors.initials: K
authors.lastname: Naruse
authors.forename: Rika
authors.initials: R
authors.lastname: Kasahara
authors.forename: Hideo
authors.initials: H
authors.lastname: Taniura
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirate
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sugiura
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kazuya
authors.initials: K
authors.lastname: Sobue
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000700:Analgesics / Q000008:administration & dosage; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D007649:Ketamine / Q000008:administration & dosage*; D015260:Neprilysin / Q000378:metabolism*; D011489:Protein Denaturation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D000700:Analgesics; D007649:Ketamine; D015260:Neprilysin