The Common Inhalation Anesthetic Isoflurane Induces Apoptosis and Increases Amyloid β Protein Levels

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Abstract

Background:

The common inhalation anesthetic isoflurane has previously been reported to enhance the aggregation and cytotoxicity of the Alzheimer disease–associated amyloid β protein (Aβ), the principal peptide component of cerebral β-amyloid deposits.

Methods:

H4 human neuroglioma cells stably transfected to express human full-length wild-type amyloid precursor protein (APP) were exposed to 2% isoflurane for 6 h. The cells and conditioned media were harvested at the end of the treatment. Caspase-3 activation, processing of APP, cell viability, and Aβ levels were measured with quantitative Western blotting, cell viability kit, and enzyme-linked immunosorbent assay sandwich. The control condition consisted of 5% CO2 plus 21% O2 and balanced nitrogen, which did not affect caspase-3 activation, cell viability, APP processing, or Aβ generation.

Results:

Two percent isoflurane caused apoptosis, altered processing of APP, and increased production of Aβ in H4 human neuroglioma cell lines. Isoflurane-induced apoptosis was independent of changes in Aβ and APP holoprotein levels. However, isoflurane-induced apoptosis was potentiated by increased levels of APP C-terminal fragments.

Conclusion:

A clinically relevant concentration of isoflurane induces apoptosis, alters APP processing, and increases Aβ production in a human neuroglioma cell line. Because altered processing of APP leading to accumulation of Aβ is a key event in the pathogenesis of Alzheimer disease, these findings may have implications for use of this anesthetic agent in individuals with excessive levels of cerebral Aβ and elderly patients at increased risk for postoperative cognitive dysfunction.

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