Inhaled anesthetics enhance oligomerization and cytotoxicity of Alzheimer disease-associated peptides. In addition to the possibility of a general mechanism for anesthetic neurotoxicity, these results call for further evaluation of the interaction between neurodegenerative disorders, dementia, and inhalational anesthesia.

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The toxicity of thapsigargin, a selective inhibitor of endoplasmic reticular Ca2+‐ATPase, was investigated in GT1‐7 cells, a murine hypothalamic cell line. Treatment of these cells with 50 or 100 nM thapsigargin greatly reduced cell viability at 24 and 48 h. These doses of thapsigargin induced a rapid rise in free cytosolic Ca2+ ([Ca2+]i), followed by a sustained increase. Addition of EGTA to chelate extracellular Ca2+ diminished somewhat the size of the initial increase of [Ca2+]i caused by thapsigargin, and abolished the sustained increase. The sustained increase could also be abolished by addition of La3+ and by SKF 96365, a drug selective for receptor‐mediated calcium entry, but not by verapamil or flunarizine. Pretreatment with 50 µM BAPTA/AM, a cytosolic Ca2+ chelator, inhibited the peak [Ca2+]i caused by thapsigargin but did not inhibit the sustained elevation of [Ca2+]i. Neither EGTA nor BAPTA/AM inhibited the cell death induced by thapsigargin. The cell death was characterized by DNA fragmentation (“laddering”), nuclear condensation and fragmentation, and was inhibited by protein synthesis inhibitor cycloheximide, all characteristic of apoptotic cell death. Overexpression of the proto‐oncogene bcl‐2 in GT1‐7 cells inhibited significantly DNA fragmentation, nuclear condensation and fragmentation, and cell death induced by thapsigargin. However, Bcl‐2 did not alter either basal [Ca2+]i or the elevation of [Ca2+]i induced by thapsigargin. Our results suggest that abnormal Ca2+ release from endoplasmic reticulum caused by thapsigargin induces GT1‐7 death by apoptosis and that this effect does not depend on Ca2+ influx from the extracellular space. Bcl‐2 inhibited apoptosis induced by thapsigargin, but the mechanism is unlikely to be inhibition of endoplasmic reticular Ca2+ release in GT1‐7 neuronal cells.

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