The Mitochondrial Pathway of Anesthetic Isoflurane-induced Apoptosis

Abstract

The common inhalation anesthetic isoflurane has been shown to induce apoptosis, which then leads to accumulation of ␤-amyloid protein, the hallmark feature of Alzheimer disease neuropathogenesis. The underlying molecular mechanism of the isoflurane-induced apoptosis is largely unknown. We, therefore, set out to assess whether isoflurane can induce apoptosis by regulating Bcl-2 family proteins, enhancing reactive oxygen species (ROS) accumulation, and activating the mitochondrial pathway of apoptosis. We performed these studies in cultured cells, primary neurons, and mice. Here we show for the first time that treatment with 2% isoflurane for 6 h can increase pro-apoptotic factor Bax levels, decrease antiapoptotic factor Bcl-2 levels, increase ROS accumulation, facilitate cytochrome c release from the mitochondria to the cytosol, induce activation of caspase-9 and caspase-3, and finally cause apoptosis as compared with the control condition. We have further found that isoflurane can increase the mRNA levels of Bax and reduce the mRNA levels of Bcl-2. The isoflurane-induced ROS accumulation can be attenuated by the intracellular calcium chelator BAPTA. Finally, the anesthetic desflurane does not induce activation of mitochondrial pathway of apoptosis. These results suggest that isoflurane may induce apoptosis through Bcl-2 family proteins-and ROS-associated mitochondrial pathway of apoptosis. These findings, which have identified at least partially the molecular mechanism by which isoflurane induces apoptosis, will promote more studies aimed at studying the potential neurotoxic effects of anesthetics.An estimated 200 million patients worldwide undergo anesthesia and surgery each year. Some clinical studies suggest that anesthesia and surgery may be associated with Alzheimer disease (AD) 3 (1-3), although different findings also exist (4, 5). Several recent studies have reported that isoflurane, one of the most commonly used inhalation anesthetics, may potentially contribute to AD neuropathogenesis by inducing apoptotic cell death and increasing ␤-amyloid protein oligomerization and accumulation in vitro and in vivo (6 -13). However, the upstream mechanism by which isoflurane induces apoptosis remains largely to be determined.Apoptosis is a programmed cell death which can be triggered by environmental and/or developmentally associated signals (14). The central components of the apoptosis process are a group of proteolytic enzymes called caspases, which can be activated by various types of stimulation (15). The extrinsic, death receptor pathway involves activation of caspase-8, which then cleaves caspase-3, leading to apoptosis (for review, see Ref. 16). The intrinsic, mitochondrial pathway is regulated by Bcl-2 family proteins, including the anti-apoptotic factor Bcl-2 and the pro-apoptotic factor Bax (for review, see Ref. 17) and involves cytochrome c release from the mitochondria to the cytosol. The released cytochrome c then activates caspase-9, which consequently induces caspase-3 activation, leading to apoptosi...

Astaxanthin Induces Mitochondria-Mediated Apoptosis in Rat Hepatocellular Carcinoma CBRH-7919 Cells

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Pathway of 3-MCPD-induced apoptosis in human embryonic kidney cells

“…Because of this, the cell is subject to strict (self) control and is eliminated without affecting neighboring cells (Chopra et al, 2010). Three main components are involved in apoptosis signal transduction: mitochondrial pathway (Zhang et al, 2010), death receptor pathway (Nebbioso et al, 2011) and endoplasmic reticulum pathway (Zhang and Kaufman, 2008). All pro-apoptotic molecules exist in intact cells and do not have to be synthesized newly (Ashkenazi, 2008).…”

The Effects of Isoflurane and Desflurane on Cognitive Function in Humans

“…[4][5][6][7][8][9][10][11] Therefore, it is conceivable that isoflurane, but not desflurane, may induce neurotoxicity, leading to POCD. Because of its chemical structure, isoflurane may be less stable than desflurane during metabolism, 19 and it is possible that the difference in metabolism between isoflurane and desflurane may contribute to the varying effects of isoflurane and desflurane on neurotoxicity and cognitive function.…”

“…[4][5][6][7][8][9][10][11] Desflurane, another commonly used inhaled anesthetic, has been reported not to have these effects. 10,12 The underlying mechanisms and functional consequences of the different effects of isoflurane and desflurane remain to be determined.…”