The Inhalation Anesthetic Desflurane Induces Caspase Activation and Increases Amyloid β-Protein Levels under Hypoxic Conditions

Zhang, Bin; Dong, Yuanlin; Zhang, Guohua; Moir, Robert D.; Xia, Weiming; Yue, Yun; Tian, Mei; Culley, Deborah J.; Crosby, Gregory; Tanzi, Rudolph E.; Xie, Zhongcong

doi:10.1074/jbc.m800199200

Cited by 90 publications

(78 citation statements)

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“…A Datex infrared gas analyzer (Puritan-Bennett, Tewksbury, MA) was used to continuously monitor the delivered concentrations of carbon dioxide, oxygen, and isoflurane or desflurane. The H4-APP cells and primary neurons were treated for 6 h with 2% isoflurane or 12% desflurane plus 21% oxygen, and 5% carbon dioxide as described by Xie et al (7) and Zhang et al (22), respectively. Staurosporine (STS, 100 M) was used as a positive control in the experiment of cytochrome c immunocytochemistry studies.…”

Section: Methodsmentioning

confidence: 99%

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The Mitochondrial Pathway of Anesthetic Isoflurane-induced Apoptosis

Zhang

Dong

et al. 2010

Journal of Biological Chemistry

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184

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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Section: Methodsmentioning

confidence: 99%

“…does not induce caspase activation and apoptosis in H4-APP cells (22). However, the other commonly used inhalation, isoflurane (7), and sevoflurane (29), at equipotent concentrations, can induce caspase activation and apoptosis.…”

Section: Journal Of Biological Chemistrymentioning

confidence: 99%

The Mitochondrial Pathway of Anesthetic Isoflurane-induced Apoptosis

Zhang

Dong

et al. 2010

Journal of Biological Chemistry

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197

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“…Cleavage of the CTF β by δ-secretase releases βA monomers into the cytosolic and extracellular space. Anesthetic exposure increases the levels of BACE and δ-secretase, thereby increasing the levels of intracellular βA and decreasing CTF β levels (57,58). Inhaled anesthetics also interact with the βA monomers to promote the formation of small, soluble oligomers (46).…”

Section: Cognitive Dysfunction and Admentioning

confidence: 99%

Postoperative cognitive dysfunction and Alzheimer disease

Işık¹

2015

Turk J Med Sci

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IntroductionThere are many comorbid diseases that become more common with ageing (1). Alzheimer disease (AD), which was described by Alois Alzheimer in 1907, is the most common form of progressive, irreversible dementia in the elderly (1-3). It affects more than 25 million people worldwide; without a major therapeutic breakthrough, its prevalence is expected to increase more than 100 million by 2050 (1-5).Worldwide, 200 million patients undergo surgery under anesthesia each year. As overall life expectancy has increased, an increasing number of elderly patients are undergoing anesthesia. In addition, elderly surgical patients are more likely to have preexisting AD or be at risk for developing it. It is well known that POCD is an important problem for the elderly and patients with probable AD (6-11). On the other hand, there are no clinical studies that clearly demonstrate that general anesthesia (GA) causes cognitive dysfunction in patients with probable AD.This review article discusses the relationship between POCD and AD based on what we found in the currently published literature. Alzheimer disease or probable Alzheimer diseaseThe diagnosis of AD is based on a positive history, neurological examination, and neuropsychological tests. The National Institute of Neurological and Communicative Disorders and the Stroke-Alzheimer's Disease and Related Disorders Association Work Group criteria for diagnosing probable AD are documentation of dementia by clinical examination, deficits in two or more cognitive domains, absence of other systemic disorders, and progressive worsening of memory (12). Another commonly used criterion, according to the DSM IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition), is the loss of at least two of the following: orientation, memory, judgment, language, or calculation (13).AD patients usually present with a subtle onset of memory loss, followed by slowly progressive dementia over the course of several years. The course of AD is variable, and cognitive impairment, personality change, psychotic symptoms, incontinence, gait and motor disturbances, seizures, and myoclonus may occur. Memory impairment is progressive and destructive. AD also increases the mortality of the affected population. Life expectancy varies between 4 and 8 years after diagnosis (14)(15)(16)(17)(18)(19)(20)(21)(22).A definitive diagnosis of AD can be made only by autopsy of a patient's brain. This neuropathological evaluation reveals diffuse atrophy of the cerebral cortex, signifying loss of neurons. Diagnostic lesions are found on histopathological evaluation of most affected areas of the brain, which reveal the presence of large numbers of extracellular β-amyloid (βA) plaques and intracellular, neurofibrillary tangles (NFTs) (1-3,21-23). Even though plaques and NFTs are often found in cognitively normal Abstract: Alzheimer disease (AD) is the most prevalent neurodegenerative disorder in elderly people. Patients with AD appear to be particularly at risk for cognitive deterioration following anesthes...

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“…Specifically, the commonly used inhalation anesthetic isoflurane has been shown to enhance Aβ oligomerization in cultured cells. 87 Isoflurane 88,90 and another commonly used inhalation anesthetic, sevoflurane, 91 but not desflurane, 92 have been shown to enhance Aβ accumulation in vivo and in vitro. Interestingly, low concentration of isoflurane alone did not increase Aβ accumulation, but the combination of this low concentration of isoflurane with nitrous oxide did increase Aβ accumulation.…”

Section: Anesthetics and Neurodegenerationmentioning

confidence: 99%