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,
Departments of *Anesthesiology,
Surgery, and
Neurobiology,
Duke University Medical Center, Durham, North Carolina
Address correspondence and reprint requests to Lisa Wise-Faberowski, MD, Duke University Medical Center, Department of Anesthesiology, Box 3094, Durham, NC 27710. Address e-mail to faber007{at}mc.duke.edu
Volatile anesthetics reduce acute excitotoxic cell death in primary neuronal/glial cultures. We hypothesized that cells protected by isoflurane against N-methyl-D-aspartate (NMDA)-induced necrosis would instead become apoptotic. Primary mixed neuronal/glial cultures prepared from fetal rat brain were exposed to dissolved isoflurane (0 mM, 0.4 mM [1.8 minimum alveolar anesthetic concentration], or 1.6 mM [7 minimum alveolar anesthetic concentration]) and NMDA (0 or 100 µM) at 37°C for 30 min. Dizocilpine (10 µM) plus 100 µM NMDA served as a positive control. Necrosis and apoptosis were assessed at 24 and/or 48 h after exposure by using Hoechst/propidium iodide staining, terminal-deoxynucleotidyl transferase end-nick labeling, DNA fragmentation enzyme-linked immunoabsorbence, and caspase-3 activity assays. NMDA increased the number of necrotic cells. Isoflurane (1.6 mM) and dizocilpine partially reduced cellular necrosis but did not increase the number of morphologically apoptotic or apoptotic-like cells resulting from exposure to 100 µM NMDA at 24 h. At 48 h, no evidence was found to indicate that cells protected by isoflurane had become apoptotic or apoptotic-like. However, cells protected by dizocilpine against necrosis showed evidence of caspase-3-mediated apoptosis. These in vitro data do not support the hypothesis that isoflurane protection against acute excitotoxic necrosis results in apoptosis.
IMPLICATIONS: Isoflurane inhibition of N-methyl-D-aspartate-induced necrotic cell death, evaluated in mixed neuronal/glial cell cultures, did not result in caspase-3-mediated apoptotic cell death. Our in vitro results failed to support the hypothesis that cells protected by isoflurane neuroprotection later deteriorate into an apoptotic state.
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