. Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology. 2004 Sep;101(3):703-9. PubMed.


Please login to recommend the paper.


  1. Waking up demented: New ideas about
    anesthesia-induced cognitive impairment

    In an intriguing paper just published in Anesthesiology, Eckenhoff et al.
    seek an explanation for the commonly observed transitory, and sometimes
    persistent, cognitive impairment that is observed following surgeries involving
    the use of inhaled anesthetics. This observation, along with results of a
    number of studies suggesting, but not proving, a link between surgery and
    increased risk of Alzheimer’s and Parkinson’s disease in the elderly, led Eckenhoff
    et al. to study whether inhaled anesthetics might have direct effects
    on amyloid-β protein (Aβ) self-assembly. To do so, the authors used a combination
    of biophysical methods to study peptide assembly. These methods
    included turbidity measurements, filtration, electron microscopy, Thioflavin
    T (ThT) binding, and size exclusion chromatography. In addition, lactate
    dehydrogenase (LDH) assays were done on PC12 cells to assess peptide-mediated
    cytotoxicity. The basic experimental design used groups including
    anesthetic alone, peptide alone, and mixtures of the two. Anesthetics included
    halothane, isoflurane, propofol, and ethanol.

    Halothane increased Aβ42 aggregation in a concentration-dependent manner.
    This anesthetic also augmented ThT binding during Aβ42 self-assembly.
    Electron microscopy of the assemblies present at the termination of these experiments
    showed fibrils and protofibrils. Examination of the amount of
    peptide filterable through a 100 kDa molecular mass membrane revealed
    that halothane-treated Aβ assembly reactions were least filterable, followed
    in rank order by isoflurane, propofol, and ethanol. Halothane also facilitated
    the formation of high molecular weight assemblies, as assessed by size
    exclusion chromatography. In addition, halothane, as well as isoflurane, potentiated
    the toxic effect of Aβ42 on PC12 cells.

    The authors conclude that inhaled anesthetics enhance oligomerization
    and cytotoxicity of Alzheimer's disease-associated peptides, and that this effect
    may underlie the clinically observed surgery (anesthetic)-associated cognitive
    impairment often observed in the elderly. This is an intriguing notion worthy
    of further study.

    How can the suggestive work of Eckenhoff et al. be placed on a rigorous
    experimental foundation? As with any structure-activity study of Aβ, the
    key requirement will be determination of the distribution of Aβ assemblies
    and a correlation of that distribution with a specific peptide-associated behavior,
    whether that behavior is biophysical (filterability, morphology, dye
    binding, turbidity) or biological (cytotoxicity). The method of peptide preparation
    used here (DMSO solubilization and dissolution into buffer) produces
    a heterogeneous population of assemblies, complicating data interpretation.
    In particular, although the role of oligomers was discussed explicitly, the
    presence of protofibrils and fibrils in the peptide preparations used precludes
    determination of the effects of anesthetics on oligomer formation and activity.
    Eckenhoff et al. may be right. However, greater confidence in the conclusions
    will come through examination of oligomer-specific assembly processes
    and effects. The application of more sophisticated spectroscopic methods
    to monitor directly anesthetic-peptide interactions would provide additional
    support for the authors’ postulations that hydrophobic interactions are central
    to the effects observed.

Make a Comment

To make a comment you must login or register.