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Yuanlin Dong, MD; Guohua Zhang, MD, PhD; Bin Zhang, MD; Robert D. Moir, PhD; Weiming Xia, PhD; Edward R. Marcantonio, MD; Deborah J. Culley, MD; Gregory Crosby, MD; Rudolph E. Tanzi, PhD; Zhongcong Xie, MD, PhD

Arch Neurol. 2009;66(5):620-631.

Objective  To assess the effects of sevoflurane, the most commonly used inhalation anesthetic, on apoptosis and β-amyloid protein (Aβ) 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.

Interventions  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 Aβ levels were assessed.

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

Author Affiliations: Genetics and Aging Research Unit, Massachusetts General Institute for Neurodegenerative Disease, Department of Neurology (Drs Dong, G. Zhang, B. Zhang, Moir, Tanzi, and Xie) and Department of Anesthesia and Critical Care (Drs Dong, G. Zhang, B. Zhang, and Xie), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Forensic Pathology, Faculty of Forensic Medicine, China Medical University, Shenyang, China (Dr G. Zhang); Department of Anesthesia, Beijing Friendship Hospital, Capital Medical University, Beijing, China (Dr B. Zhang); and Center for Neurological Diseases, Harvard Institute of Medicine and Harvard Medical School (Dr Xia), Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School (Dr Marcantonio), and Department of Anesthesia, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts (Drs Culley and Crosby).

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