Isoflurane-Induced Caspase-3 Activation Is Dependent on Cytosolic Calcium and Can Be Attenuated by Memantine

Zhang, Guohua; Dong, Yuanlin; Zhang, Bin; Ichinose, Fumito; Wu, Xu; Culley, Deborah J.; Crosby, Gregory; Tanzi, Rudolph E.; Xie, Zhongcong

doi:10.1523/jneurosci.5694-07.2008

Cited by 106 publications

(92 citation statements)

References 68 publications

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“…Treatment with isoflurane increased IL-6 in H4 cells. These data, together with our previous findings that isoflurane increases cytosolic calcium, 17 mitochondrial dysfunction, 7 caspase-3 activation, 31 and Ab accumulation 31 in H4 cells, suggested that we could use these cells to perform mechanistic studies. We found that isoflurane increased NF-kB in nucleus, but not in whole cells.…”

Section: Discussionmentioning

confidence: 54%

“…A Datex infrared gas analyser (Puritan-Bennett, Tewksbury, MA, USA) was used to continuously monitor the delivered CO 2 , O 2 , and isoflurane concentrations. We treated the cells with 2% isoflurane or 4.1% sevoflurane for 6 h in serum free media, 33 34 which has been shown to increase cytosolic calcium, 17 caspase-3 activation, 31 Ab accumulation, 31 and mitochondrial dysfunction. 7 In some studies, the cells were treated with 10 mM PDTC 35 (Sigma, St. Louis, MO, USA) or 10 mM 2-DG 18 (Sigma) 1 h before treatment with 2% isoflurane.…”

Section: H4 Human Neuroglioma Cellsmentioning

confidence: 99%

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Isoflurane and sevoflurane increase interleukin-6 levels through the nuclear factor-kappa B pathway in neuroglioma cells

Zhang

Yang

et al. 2013

British Journal of Anaesthesia

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143

102

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Section: Discussionmentioning

confidence: 54%

Section: H4 Human Neuroglioma Cellsmentioning

confidence: 99%

Isoflurane and sevoflurane increase interleukin-6 levels through the nuclear factor-kappa B pathway in neuroglioma cells

Zhang

Yang

et al. 2013

British Journal of Anaesthesia

Self Cite

143

102

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“…19), we next asked whether the isoflurane-induced ROS accumulation is dependent on the cytosol calcium levels. Previous studies have shown that intracellular calcium chelator BAPTA can attenuate the isoflurane-induced caspase-3 activation in H4-APP cells (18). We therefore set out to determine the effects of BAPTA on the isoflurane-induced ROS accumulation by fluorescence assay in the H4-APP cells.…”

Section: Isoflurane Increases Bax Levels In H4-app Cells and Primarymentioning

confidence: 99%

The Mitochondrial Pathway of Anesthetic Isoflurane-induced Apoptosis

Zhang

Dong

et al. 2010

Journal of Biological Chemistry

186

197

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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...

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“…Isoflurane exposure has been shown to cause cell damage in various neuronal and non-neuronal tissues and cells, including hippocampal slices (Wise-Faberowski et al, 2005), lymphocytes Yang et al, 2008), neuroglioma cells (Xie et al, 2007;Zhang et al, 2008), hepatocytes (Malledant et al, 1990), gingival fibroblasts (Chang and Chou, 2001), the PC12 neurosecretory cell line Liang et al, 2008), and striatal neurons . Interestingly, these cells have different intrinsic vulnerability to anesthetic toxicity, with lymphocytes generally being more vulnerable than neurons (Wei et al, 2005Liang et al, 2008).…”

mentioning

confidence: 99%

Anesthetic-Induced Neurodegeneration Mediated via Inositol 1,4,5-Trisphosphate Receptors

Zhao

Chen

et al. 2010

The Journal of Pharmacology and Experimental Therapeutics

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The commonly used general anesthetic isoflurane induces widespread neurodegeneration in the developing mammalian brain through poorly understood mechanisms. We have investigated whether excessive Ca 2ϩ release from the endoplasmic reticulum via overactivation of inositol 1,4,5-trisphosphate receptors (InsP 3 Rs) is a contributing factor in such neurodegeneration in rodent primary cultured neurons and developing rat brain. We also investigated the correlation between isoflurane exposure and cognitive decline in rats at 1 month of age. Our results show that isoflurane increases cytosolic calcium in the primary cortical neurons through release from the endoplasmic reticulum and influx from the extracellular space. Pharmacological inhibition of InsP 3 R activity and knockdown of its expression nearly abolishes the isoflurane-mediated elevation of the cytosolic calcium concentration and cell death in rodent primary cortical and hippocampal neurons. Inhibition of InsP 3 R activity by its antagonist xestospongin C significantly inhibits neurodegeneration induced by isoflurane at clinically used concentration in the developing brain of postnatal day 7 rats. Moreover, our results show that isoflurane activates ␤-site amyloid ␤ precursor protein-cleaving enzyme via activation of the InsP 3 R. We also noted that mice exposed to isoflurane during early postnatal development showed transient memory and learning impairments, which did not correlate well with the noted neuropathological defects. Taken together, our results suggest that Ca 2ϩ dysregulation through overactivation of the InsP 3 R may be a contributing factor in the mechanism of isoflurane-induced neurodegeneration in rodent neuronal cell culture and during brain development.

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Isoflurane-Induced Caspase-3 Activation Is Dependent on Cytosolic Calcium and Can Be Attenuated by Memantine

Cited by 106 publications

References 68 publications

Isoflurane and sevoflurane increase interleukin-6 levels through the nuclear factor-kappa B pathway in neuroglioma cells

Isoflurane and sevoflurane increase interleukin-6 levels through the nuclear factor-kappa B pathway in neuroglioma cells

The Mitochondrial Pathway of Anesthetic Isoflurane-induced Apoptosis

Anesthetic-Induced Neurodegeneration Mediated via Inositol 1,4,5-Trisphosphate Receptors

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