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J. Biol. Chem., Vol. 283, Issue 18, 11866-11875, May 2, 2008

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The Inhalation Anesthetic Desflurane Induces Caspase Activation and Increases Amyloid β-Protein Levels under Hypoxic Conditions^*

Bin Zhang^¶1, Yuanlin Dong¹, Guohua Zhang^||, Robert D. Moir, Weiming Xia^**, Yun Yue, Ming Tian^¶, Deborah J. Culley, Gregory Crosby, Rudolph E. Tanzi², and Zhongcong Xie³

From the Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129-2060, the Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, the ^¶Department of Anesthesia, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China, the ^||Department of Forensic Pathology, Faculty of Forensic Medicine, China Medical University, 92 Beier Road, Heping District, Shenyang 110001, China, the ^**Center for Neurological Diseases, Harvard Institute of Medicine and Harvard Medical School, Boston, Massachusetts 02115, the Department of Anesthesia, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100050, China, and the Department of Anesthesia, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115

Perioperative factors including hypoxia, hypocapnia, and certain anesthetics have been suggested to contribute to Alzheimer disease (AD) neuropathogenesis. Desflurane is one of the most commonly used inhalation anesthetics. However, the effects of desflurane on AD neuropathogenesis have not been previously determined. Here, we set out to assess the effects of desflurane and hypoxia on caspase activation, amyloid precursor protein (APP) processing, and amyloid β-protein (Aβ) generation in H4 human neuroglioma cells (H4 naïve cells) as well as those overexpressing APP (H4-APP cells). Neither 12% desflurane nor hypoxia (18% O₂) alone affected caspase-3 activation, APP processing, and Aβ generation. However, treatment with a combination of 12% desflurane and hypoxia (18% O₂) (desflurane/hypoxia) for 6 h induced caspase-3 activation, altered APP processing, and increased Aβ generation in H4-APP cells. Desflurane/hypoxia also increased levels of β-site APP-cleaving enzyme in H4-APP cells. In addition, desflurane/hypoxia-induced Aβ generation could be reduced by the broad caspase inhibitor benzyloxycarbonyl-VAD. Finally, the Aβ aggregation inhibitor clioquinol and -secretase inhibitor L-685,458 attenuated caspase-3 activation induced by desflurane/hypoxia. In summary, desflurane can induce Aβ production and caspase activation, but only in the presence of hypoxia. Pending in vivo confirmation, these data may have profound implications for anesthesia care in elderly patients, and especially those with AD.

Received for publication, January 9, 2008 , and in revised form, February 11, 2008.

^* This work was supported by Grant R37MH 60009 from the National Institutes of Health and the Cure Alzheimer's Fund (to R. E. T.) and by Grant K08 NS048140 from the National Institutes of Health, and Jahnigen Career Development Award from the American Geriatrics Society, an Investigator Initiated research grant from the Alzheimer's Association, and the William Milton Fund (Harvard University) (to Z. X.). The cost of the anesthetic desflurane and partial financial support of Yuanlin Dong and Bin Zhang were generously provided by the Department of Anesthesia and Critical Care in Massachusetts General Hospital and Harvard Medical School. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed: Genetics and Aging Research Unit, Massachusetts General Hospital/Harvard Medical School, 114 16th St., C3009, Charlestown, MA 02129-4404. Tel.: 617-726-6845; Fax: 617-724-1949; E-mail: tanzi{at}helix.mgh.harvard.edu. ³ To whom correspondence may be addressed: Genetics and Aging Research Unit, Dept. of Neurology, Dept. of Anesthesia and Critical Care, Massachusetts General Hospital/Harvard Medical School, 114 16th St., 3750, Charlestown, MA 02129-4404. Tel.: 617-724-9308; Fax: 617-724-1823; E-mail: zxie{at}partners.org.

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