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From the Department of Anesthesiology and Critical Care, University of Pennsylvania, Philadelphia, Pennsylvania.
Address correspondence and reprint requests to Huafeng Wei, MD, PhD, Department of Anesthesiology and Critical Care, University of Pennsylvania, 305 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104. Address e-mail to weih{at}uphs.upenn.edu.
BACKGROUND: Isoflurane, a commonly used inhaled anesthetic, induces apoptosis in rat pheochromocytoma neurosecretory cells (PC12) in a concentration- and time-dependent manner via an as yet unknown mechanism. We hypothesize that isoflurane induces apoptosis by causing abnormal calcium release from the endoplasmic reticulum (ER) via activation of inositol 1,4,5-trisphosphate (IP3) receptors. A presenilin-1 (PS1) mutation associated with familial Alzheimer’s disease was shown to increase the activity of IP3 receptors, and therefore may render cells vulnerable to isoflurane-induced cytotoxicity. Sevoflurane and desflurane have less ability to disrupt intracellular calcium homeostasis; and thus we predict they will cause less cytotoxicity.
METHODS: PC12 cells transfected with wild type, vector alone (Vector) or mutated PS1 (L286V) were treated with equivalent of 1 MAC of isoflurane, sevoflurane, and desflurane for 12 h. Mitochondria redox activity (MTT reduction) and lactate dehydrogenase release assays were performed to evaluate cell viability. Changes of calcium concentration in cytosolic space ([Ca2+]c) and production of reactive oxygen species (ROS) were determined after exposing different types of cells to various inhaled anesthetics. We also determined the effects of IP3 receptor antagonist xestospongin C on isoflurane-induced cytotoxicity and calcium release from the ER in L286V PC12 cells, and in rat primary cortical neurons.
RESULTS: Isoflurane at 1 MAC for 12 h induced cytotoxicity in L286V but not wild type or vector PC12 cells, and also caused greater and faster increase of peak [Ca2+]c in the L286V cells. Xestospongin C significantly attenuated isoflurane cytotoxicity in both L286V cells and primary cortical neurons and inhibited the calcium release from the ER in L286V cells. Isoflurane did not induce significant changes of ROS production in any type of PC12 cells. Sevoflurane and desflurane at equivalent exposure to isoflurane did not induce similar cytotoxicity or increase of peak [Ca2+]c in L286V PC12 cells.
CONCLUSION: Our results show that the L286V PS1 mutation augments the isoflurane-induced [Ca2+]c increase via calcium release from intracellular stores which, in turn, renders the cells vulnerable to isoflurane neurotoxicity. ROS production was not involved in isoflurane-induced neurotoxicity. Sevoflurane and desflurane, at equivalent exposure to isoflurane, did not induce a similar increase of [Ca2+]c or neurotoxicity in L286V PC12 cells.
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