Isoflurane-induced caspase-3 activation is dependent on cytosolic calcium and can be attenuated by memantine.
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-beta protein (Abeta) 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 IP(3) 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 microM), and RNAi silencing of IP(3) receptor, NMDA receptor, or SERCA1 attenuated caspase-3 activation. Memantine (4 microM) 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.
Zhang
Guohua
G
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129-2060, USA.
Dong
Yuanlin
Y
Zhang
Bin
B
Ichinose
Fumito
F
Wu
Xu
X
Culley
Deborah J
DJ
Crosby
Gregory
G
Tanzi
Rudolph E
RE
Xie
Zhongcong
Z
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism*; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005260:Female; D006801:Humans; D007530:Isoflurane / Q000494:pharmacology*; D008559:Memantine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL
D061945:Caspase Inhibitors; D007530:Isoflurane; D053148:Caspase 3; D002118:Calcium; D008559:Memantine