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The Journal of Neuroscience, April 23, 2008, 28(17):4551-4560; doi:10.1523/JNEUROSCI.5694-07.2008

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Neurobiology of Disease
Isoflurane-Induced Caspase-3 Activation Is Dependent on Cytosolic Calcium and Can Be Attenuated by Memantine

Guohua Zhang,^1,2,3 * Yuanlin Dong,^1,2 * Bin Zhang,^1,2,4 Fumito Ichinose,² Xu Wu,^1,2,3 Deborah J. Culley,⁵ Gregory Crosby,⁵ Rudolph E. Tanzi,¹ and Zhongcong Xie^1,2

¹Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129-2060, ²Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, ³Department of Forensic Pathology, Faculty of Forensic Medicine, China Medical University, Heping District, 110001 Shenyang, China, ⁴Department of Anesthesia, Beijing Friendship Hospital, Capital Medical University, 100050 Beijing, China, and ⁵Department of Anesthesia, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to either of the following: Dr. Rudolph E. Tanzi, Professor of Neurology (Neuroscience), Director, Genetics and Aging Research Unit, Massachusetts General Hospital/Harvard Medical School, 114 16th Street, C3009, Charlestown, MA 02129-4404, Email: tanzi{at}helix.mgh.harvard.edu; or Dr. Zhongcong Xie, Assistant Professor of Anesthesia, Department of Anesthesia and Critical Care, Genetics and Aging Research Unit, Massachusetts General Hospital/Harvard Medical School, 114 16th Street, 3750, Charlestown, MA 02129-4404, Email: zxie{at}partners.org

Increasing evidence indicates that caspase activation and apoptosis are associated with a variety of neurodegenerative disorders, including Alzheimer's disease. We reported that anesthetic isoflurane can induce apoptosis, alter processing of the amyloid precursor protein (APP), and increase amyloid-β protein (Aβ) generation. However, the mechanism by which isoflurane induces apoptosis is primarily unknown. We therefore set out to assess effects of extracellular calcium concentration on isoflurane-induced caspase-3 activation in H4 human neuroglioma cells stably transfected to express human full-length APP (H4-APP cells). In addition, we tested effects of RNA interference (RNAi) silencing of IP₃ receptor, NMDA receptor, and endoplasmic reticulum (ER) calcium pump, sacro-/ER calcium ATPase (SERCA1). Finally, we examined the effects of the NMDA receptor partial antagonist, memantine, in H4-APP cells and brain tissue of naive mice. EDTA (10 mM), BAPTA (10 µM), and RNAi silencing of IP₃ receptor, NMDA receptor, or SERCA1 attenuated capase-3 activation. Memantine (4 µM) inhibited isoflurane-induced elevations in cytosolic calcium levels and attenuated isoflurane-induced caspase-3 activation, apoptosis, and cell viability. Memantine (20 mg/kg, i.p.) reduced isoflurane-induced caspase-3 activation in brain tissue of naive mice. These results suggest that disruption of calcium homeostasis underlies isoflurane-induced caspase activation and apoptosis. We also show for the first time that the NMDA receptor partial antagonist, memantine, can prevent isoflurane-induced caspase-3 activation and apoptosis in vivo and in vitro. These findings, indicating that isoflurane-induced caspase activation and apoptosis are dependent on cytosolic calcium levels, should facilitate the provision of safer anesthesia care, especially for Alzheimer's disease and elderly patients.

Key words: Alzheimer's disease; anesthesia; isoflurane; apoptosis; calcium; memantine

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Received Oct. 21, 2007; revised March 21, 2008; accepted March 26, 2008.

Correspondence should be addressed to either of the following: Dr. Rudolph E. Tanzi, Professor of Neurology (Neuroscience), Director, Genetics and Aging Research Unit, Massachusetts General Hospital/Harvard Medical School, 114 16th Street, C3009, Charlestown, MA 02129-4404, Email: tanzi{at}helix.mgh.harvard.edu; or Dr. Zhongcong Xie, Assistant Professor of Anesthesia, Department of Anesthesia and Critical Care, Genetics and Aging Research Unit, Massachusetts General Hospital/Harvard Medical School, 114 16th Street, 3750, Charlestown, MA 02129-4404, Email: zxie{at}partners.org

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