Propofol and Thiopental Suppress Amyloid Fibril Formation and GM1 Ganglioside Expression through the γ-Aminobutyric Acid A Receptor

Abstract

Background: The incidence of Alzheimer disease may increase after surgical interventions. Amyloid β-protein (Aβ) fibrillogenesis, which is closely related to Alzheimer disease, is reportedly accelerated by exposure to anesthetics. However, the effects of GM1 ganglioside (GM1) on Αβ fibrillogenesis have not yet been reported. The current study was designed to examine whether the anesthetics propofol and thiopental are associated with Αβ assembly and GM1 expression on the neuronal cell surface. Methods: PC12N cells and cultured neuronal cells were treated with propofol or thiopental, and GM1 expression in treated and untreated cells was determined by the specific binding of horseradish peroxidase-conjugated cholera toxin subunit B (n = 5). The effects of an inhibitor of the γ-aminobutyric acid A receptor was also examined (n= 5). In addition, the effects of the anesthetics on GM1 liposome-induced Αβ assembly were investigated (n = 5). Finally, the neurotoxicity of the assembled Αβ fibrils was studied by the lactate dehydrogenase release assay (n = 6). Results: Propofol (31.2±4.7%) and thiopental (34.6±10.5%) decreased GM1 expression on the cell surface through the γ-aminobutyric acid A receptor. The anesthetics inhibited Αβ fibril formation from soluble Αβ in cultured neurons. Moreover, propofol and thiopental suppressed GM1-induced fibril formation in a cell-free system (propofol, 75.8±1.9%; thiopental, 83.6±1.9%) and reduced the neurotoxicity of a mixture containing Aβ and GM1 liposomes (propofol, 35.3±16.4%; thiopental, 21.3±11.6%). Conclusions: Propofol and thiopental have direct and indirect inhibitory effects on Αβ fibrillogenesis.

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

“…We have previously reported that insulin regulates the expression and distribution of GM1 in neuronal DRM through PI3K [28]. Moreover, our recent study found that propofol and thiopental inhibited the formation of Аb assemblies by decreasing GM1 expression in neuronal DRM through the GABAAR [22]. In the present study, we found that GM1 expression in neuronal DRM and synaptosomes was reduced by midazolam and that these effects were mediated through the GABAAR.…”

“…The present Аb assembly experiments were performed in a cell-free system using seed-free Аb solutions and GM1 liposomes. Recently, we found that propofol and thiopental inhibited the formation of GM1 liposome-induced Аb assemblies from soluble Аb [22]. Although further investigation is required, the findings of the present study indicate that midazolam directly inhibits the formation of GM1 liposome-induced Аb assemblies through molecular interactions (Fig.…”

“…As a result, it was found that neuronal GM1 expression was significantly decreased by midazolam treatment in a concentration-dependent manner (Fig. 1B); however, it was not affected by treatment with 0.01% dimethyl sulfoxide (DMSO) solution, as a previous reported (control; data not shown) [22]. To investigate midazolam's mechanism of action, neurons were pretreated with bicuculline, a GABAAR inhibitor, in the presence or absence of midazolam.…”

Leptin inhibits amyloid β‐protein fibrillogenesis by decreasing GM1 gangliosides on the neuronal cell surface through PI3K/Akt/mTOR pathway

“…) and that PDMP, insulin, propofol, and thiopental inhibited the GM1 expression levels in PC12N cells (Yamamoto et al . , , ). To investigate whether GM1 synthesis is inhibited by leptin, we pre‐treated neurons with chloroquine before leptin treatment, following which the cells were treated with leptin in the presence of chloroquine.…”

“…Furthermore, we recently found that insulin, propofol, and thiopental inhibited the formation of Aβ fibrils on the neuronal cell surface through the reduction in GM1 expression in the detergent‐resistant membrane microdomains (DRMs) of neuronal membranes (Yamamoto et al . , ), whereas insulin resistance had the reverse effect (Yamamoto et al . ).…”