The common inhalational anesthetic sevoflurane induces apoptosis and increases beta-amyloid protein levels.
OBJECTIVE
To assess the effects of sevoflurane, the most commonly used inhalation anesthetic, on apoptosis and beta-amyloid protein (Abeta) levels in vitro and in vivo. Subjects Naive mice, H4 human neuroglioma cells, and H4 human neuroglioma cells stably transfected to express full-length amyloid precursor protein.


METHODS
Human H4 neuroglioma cells stably transfected to express full-length amyloid precursor protein were exposed to 4.1% sevoflurane for 6 hours. Mice received 2.5% sevoflurane for 2 hours. Caspase-3 activation, apoptosis, and Abeta levels were assessed.


RESULTS
Sevoflurane induced apoptosis and elevated levels of beta-site amyloid precursor protein-cleaving enzyme and Abeta in vitro and in vivo. The caspase inhibitor Z-VAD decreased the effects of sevoflurane on apoptosis and Abeta. Sevoflurane-induced caspase-3 activation was attenuated by the gamma-secretase inhibitor L-685,458 and was potentiated by Abeta. These results suggest that sevoflurane induces caspase activation which, in turn, enhances beta-site amyloid precursor protein-cleaving enzyme and Abeta levels. Increased Abeta levels then induce further rounds of apoptosis.


CONCLUSIONS
These results suggest that inhalational anesthetic sevoflurane may promote Alzheimer disease neuropathogenesis. If confirmed in human subjects, it may be prudent to caution against the use of sevoflurane as an anesthetic, especially in those suspected of possessing excessive levels of cerebral Abeta.
Genetics and Aging Research Unit, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Yuanlin
Y
Dong
Guohua
G
Zhang
Bin
B
Zhang
Robert D
RD
Moir
Weiming
W
Xia
Edward R
ER
Marcantonio
Deborah J
DJ
Culley
Gregory
G
Crosby
Rudolph E
RE
Tanzi
Zhongcong
Z
Xie
D000544:Alzheimer Disease / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053148:Caspase 3 / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008738:Methyl Ethers / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D058225:Plaque, Amyloid / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000077149:Sevoflurane; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D018685:Anesthetics, Inhalation; D004791:Enzyme Inhibitors; D008738:Methyl Ethers; D000077149:Sevoflurane; D053829:Amyloid Precursor Protein Secretases; D053148:Caspase 3