Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory

Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, USA.
Annals of Neurology (Impact Factor: 9.98). 05/2012; 71(5):687-98. DOI: 10.1002/ana.23536
Source: PubMed


There are approximately 8.5 million Alzheimer disease (AD) patients who need anesthesia and surgery care every year. The inhalation anesthetic isoflurane, but not desflurane, has been shown to induce caspase activation and apoptosis, which are part of AD neuropathogenesis, through the mitochondria-dependent apoptosis pathway. However, the in vivo relevance, underlying mechanisms, and functional consequences of these findings remain largely to be determined.
We therefore set out to assess the effects of isoflurane and desflurane on mitochondrial function, cytotoxicity, learning, and memory using flow cytometry, confocal microscopy, Western blot analysis, immunocytochemistry, and the fear conditioning test.
Here we show that isoflurane, but not desflurane, induces opening of mitochondrial permeability transition pore (mPTP), increase in levels of reactive oxygen species, reduction in levels of mitochondrial membrane potential and adenosine-5'-triphosphate, activation of caspase 3, and impairment of learning and memory in cultured cells, mouse hippocampus neurons, mouse hippocampus, and mice. Moreover, cyclosporine A, a blocker of mPTP opening, attenuates isoflurane-induced mPTP opening, caspase 3 activation, and impairment of learning and memory. Finally, isoflurane may induce the opening of mPTP via increasing levels of reactive oxygen species.
These findings suggest that desflurane could be a safer anesthetic for AD patients as compared to isoflurane, and elucidate the potential mitochondria-associated underlying mechanisms, and therefore have implications for use of anesthetics in AD patients, pending human study confirmation.

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Available from: Yiying Zhang, Oct 02, 2015
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    • "Similarly, the intravenous general anesthetic, propofol, at clinically relevant concentrations and durations, has also been shown to cause significant apoptosis in the developing brain [4], [5], [46], [47], and associated cognitive dysfunction [7]. While comparisons of different inhaled anesthetics to induce neuroapoptosis in the developing brain and subsequent cognitive dysfunction have been undertaken [10], [12], [48], [49], such a comparison has not been carried out between an inhalational anesthetic and propofol. Because propofol is the most commonly used induction agent for general anesthesia and isoflurane is the most widely studied inhalational general anesthetic, this study compares the potency of propofol and isoflurane to cause neurodegeneration in the developing rodent brain and associated changes in cognitive function. "
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    ABSTRACT: Background While previous studies have demonstrated neuronal apoptosis and associated cognitive impairment after isoflurane or propofol exposure in neonatal rodents, the effects of these two anesthetics have not been directly compared. Here, we compare and contrast the effectiveness of isoflurane and propofol to cause neurodegeneration in the developing brain and associated cognitive dysfunction. Methods Seven-day-old mice were used. Mice in the isoflurane treatment group received 6 h of 1.5% isoflurane, while mice in propofol treatment group received one peritoneal injection (150 mg/kg), which produced persistent anesthesia with loss of righting for at least 6 h. Mice in control groups received carrying gas or a peritoneal injection of vehicle (intralipid). At 6 h after anesthetic treatment, a subset of each group was sacrificed and examined for evidence of neurodegeneration, using plasma levels of S100β, and apoptosis using caspase-3 immunohistochemistry in the cerebral cortex and hippocampus and Western blot assays of the cortex. In addition, biomarkers for inflammation (interleukin-1, interleukin-6, and tumor necrosis factor alpha) were examined with Western blot analyses of the cortex. In another subset of mice, learning and memory were assessed 32 days after the anesthetic exposures using the Morris water maze. Results Isoflurane significantly increased plasma S100β levels compared to controls and propofol. Both isoflurane and propofol significantly increased caspase-3 levels in the cortex and hippocampus, though isoflurane was significantly more potent than propofol. However, there were no significant differences in the inflammatory biomarkers in the cortex or in subsequent learning and memory between the experimental groups. Conclusion Both isoflurane and propofol caused significant apoptosis in the mouse developing brain, with isoflurane being more potent. Isoflurane significantly increased levels of the plasma neurodegenerative biomarker, S100β. However, these neurodegenerative effects of isoflurane and propofol in the developing brain were not associated with effects on inflammation or with cognitive dysfunction in later life.
    PLoS ONE 06/2014; 9(6):e99171. DOI:10.1371/journal.pone.0099171 · 3.23 Impact Factor
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    • "Interestingly, despite experimental design differences , this protective effect could also be a factor in the repetitive exposures performed here. However, negative effects to isoflurane exposure were also described (Mandal and Fodale 2009; Zhang et al. 2012, 2013), and more studies are needed to clarify this aspect, most of all regarding the link between memory and behavioral impairment and the site of cortical histological changes. "
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    ABSTRACT: The use of anesthetics and sedatives has been suggested to be a contributor to Alzheimer's disease neuropathogenesis. We wanted to address the in vivo relevance of those substances in the Tg2576 Alzheimer's mouse model. Tg7526 mice were anesthesia-sedated for 90 min once a week for 4 weeks. Y maze, Congo Red, and amyloid beta (Aβ) immunochemistry were performed. We did not find any significant change in the navigation behavior of the exposed mice compared to the controls. Significantly less deposition of Aβ in the CA1 area of the hippocampus and frontal cortex of mice exposed to isoflurane, propofol, diazepam, ketamine, and pentobarbital was observed. In the dentate gyrus, Aβ deposition was significantly greater in the group treated with pentobarbital. Congo Red staining evidenced significantly fewer fibrils in the cortex of mice exposed to diazepam, ketamine, or pentobarbital. The adopted repetitive exposure did not cause a significant detriment in Tg7526 mouse.
    Neurotoxicity Research 06/2014; 26(4). DOI:10.1007/s12640-014-9478-8 · 3.54 Impact Factor
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    • "Some anesthetics, e.g., isoflurane, have been shown to induce neurotoxicity and neurobehavioral deficits in vitro and in vivo[25,33-46]. Therefore, the current findings that propofol attenuated Aβ levels in brain tissues of mice suggested that more studies are needed to assess whether propofol could be a better choice when providing anesthesia care for AD patients or senior patients who are vulnerable to develop postoperative cognitive dysfunction. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia. At the present time, however, AD still lacks effective treatments. Our recent studies showed that chronic treatment with anesthetic propofol attenuated brain caspase-3 activation and improved cognitive function in aged mice. Accumulation of beta-amyloid protein (Abeta) is a major component of the neuropathogenesis of AD dementia and cognitive impairment. We therefore set out to determine the effects of chronic treatment with propofol on Abeta levels in brain tissues of aged mice. Propofol (50 mg/kg) was administrated to aged (18 month-old) wild-type mice once a week for 8 weeks. The brain tissues of mice were harvested one day after the final propofol treatment. The harvested brain tissues were then subjected to enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. Here we report that the propofol treatment reduced Abeta (Abeta40 and Abeta42) levels in the brain tissues of the aged mice. Moreover, the propofol treatment decreased the levels of beta-site amyloid precursor protein cleaving enzyme (the enzyme for Abeta generation), and increased the levels of neprilysin (the enzyme for Abeta degradation) in the brain tissues of the aged mice. These results suggested that the chronic treatment with propofol might reduce brain Abeta levels potentially via decreasing brain levels of beta-site amyloid precursor protein cleaving enzyme, thus decreasing Abeta generation; and via increasing brain neprilysin levels, thus increasing Abeta degradation. These preliminary findings from our pilot studies have established a system and postulated a new hypothesis for future research.
    Translational Neurodegeneration 04/2014; 3(1):8. DOI:10.1186/2047-9158-3-8
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