Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity.
BACKGROUND
The majority of surgical patients receive inhaled anesthetics, principally small haloalkanes and haloethers. Long-term cognitive problems occur in the elderly subsequent to anesthesia and surgery, and previous surgery might also be a risk factor for neurodegenerative disorders like Alzheimer and Parkinson disease. The authors hypothesize that inhaled anesthetics contribute to these effects through a durable enhancement of peptide oligomerization.


METHODS
Light scattering, filtration assays, electron microscopy, fluorescence spectroscopy and size-exclusion chromatography was used to characterize the concentration-dependent effects of halothane, isoflurane, propofol, and ethanol on amyloid beta peptide oligomerization. Pheochromocytoma cells were used to characterize cytotoxicity of amyloid oligomers with and without the above anesthetics.


RESULTS
Halothane and isoflurane enhanced amyloid beta oligomerization rates and pheochromocytoma cytotoxicity in vitro through a preference for binding small oligomeric species. Ethanol and propofol inhibited oligomerization at low concentration but enhanced modestly at very high concentration. Neither ethanol nor propofol enhanced amyloid beta toxicity in pheochromocytoma cells.


CONCLUSIONS
Inhaled anesthetics enhance oligomerization and cytotoxicity of Alzheimer disease-associated peptides. In addition to the possibility of a general mechanism for anesthetic neurotoxicity, these results call for further evaluation of the interaction between neurodegenerative disorders, dementia, and inhalational anesthesia.
Department of Anesthesia, University of Pennsylvania, Philadelphia, Pennsylvania 19104-4283, USA. roderic.eckenhoff@uphs.upenn.edu
Roderic G
RG
Eckenhoff
Jonas S
JS
Johansson
Huafeng
H
Wei
Anna
A
Carnini
Baobin
B
Kang
Wenlin
W
Wei
Ravindernath
R
Pidikiti
Jason M
JM
Keller
Maryellen F
MF
Eckenhoff
D000310:Adrenal Gland Neoplasms / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D002850:Chromatography, Gel; D000431:Ethanol / Q000494:pharmacology; D005456:Fluorescent Dyes; D006221:Halothane / Q000494:pharmacology; D007091:Image Processing, Computer-Assisted; D007530:Isoflurane / Q000494:pharmacology; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008854:Microscopy, Electron; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D010673:Pheochromocytoma / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015742:Propofol / Q000494:pharmacology; D051381:Rats; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D018685:Anesthetics, Inhalation; D002492:Central Nervous System Depressants; D005456:Fluorescent Dyes; D009842:Oligopeptides; D000431:Ethanol; D007530:Isoflurane; D007770:L-Lactate Dehydrogenase; D006221:Halothane; D015742:Propofol