The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo.
OBJECTIVE
An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease. The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis, and to increase levels and aggregation of Alzheimer's disease-associated amyloid beta-protein (Abeta) in cultured cells. However, the in vivo relevance has not been addressed.


METHODS
We therefore set out to determine effects of isoflurane on caspase activation and levels of beta-site amyloid precursor protein-cleaving enzyme (BACE) and Abeta in naive mice, using Western blot, immunohistochemistry, and reverse transcriptase polymerase chain reaction.


RESULTS
Here we show for the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for 2 hours) leads to caspase activation and modest increases in levels of BACE 6 hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, and increases levels of BACE and Abeta up to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the Abeta aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo.


CONCLUSIONS
Given that transient insults to brain may lead to long-term brain damage, these findings suggest that isoflurane may promote Alzheimer's disease neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending human study confirmation.
Xie
Zhongcong
Z
Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA. zxie@partners.org
Culley
Deborah J
DJ
Dong
Yuanlin
Y
Zhang
Guohua
G
Zhang
Bin
B
Moir
Robert D
RD
Frosch
Matthew P
MP
Crosby
Gregory
G
Tanzi
Rudolph E
RE
D016229:Amyloid beta-Peptides / Q000032:analysis / Q000096:biosynthesis*; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D020169:Caspases / Q000032:analysis / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D007530:Isoflurane / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL
D016229:Amyloid beta-Peptides; D018685:Anesthetics, Inhalation; D007530:Isoflurane; D020169:Caspases