The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid beta protein levels.
BACKGROUND
The common inhalation anesthetic isoflurane has previously been reported to enhance the aggregation and cytotoxicity of the Alzheimer disease-associated amyloid beta protein (Abeta), the principal peptide component of cerebral beta-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 Abeta 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 Abeta generation.


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


CONCLUSIONS
A clinically relevant concentration of isoflurane induces apoptosis, alters APP processing, and increases Abeta production in a human neuroglioma cell line. Because altered processing of APP leading to accumulation of Abeta 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 Abeta and elderly patients at increased risk for postoperative cognitive dysfunction.
Xie
Zhongcong
Z
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129-4404, USA.
Dong
Yuanlin
Y
Maeda
Uta
U
Alfille
Paul
P
Culley
Deborah J
DJ
Crosby
Gregory
G
Tanzi
Rudolph E
RE
D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005910:Glioma / Q000378:metabolism; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D014280:Triglycerides / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018685:Anesthetics, Inhalation; D009419:Nerve Tissue Proteins; D014280:Triglycerides; D005680:gamma-Aminobutyric Acid; C057077:1,2-dilinolenoyl-3-(4-aminobutyryl)propane-1,2,3-triol; D007530:Isoflurane; D020169:Caspases