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Anesthetic isoflurane has been shown to promote Alzheimer's disease (AD) neuropathogenesis by inducing caspase activation and accumulation of β-amyloid (Aβ). Phosphorylation of tau protein is another important feature of AD neuropathogenesis. However, the effects of isoflurane on phosphorylated tau levels remain largely to be determined. We therefore set out to determine whether isoflurane can increase phosphorylated tau levels. 5 to 8 month-old wild-type and AD transgenic mice [B6.Cg-Tg (APPswe, PSEN1dE9)85Dbo/J] were treated with 1.4% isoflurane for two hours. The mice brain tissues were harvested at six, 12 and 24 hours after the anesthesia. For the in vitro studies, primary neurons from wild-type and the AD transgenic mice were exposed to 2% isoflurane for six hours, and were harvested at the end of anesthesia. The harvested brain tissues and neurons were subjected to Western blot analysis by which the levels of phosphorylated tau protein at Serine 262 (Tau-PS262) were determined. Here we show that the isoflurane anesthesia increased Tau-PS262 levels in brain tissues and primary neurons from the wild-type and AD transgenic mice. Moreover, the isoflurane anesthesia may induce a greater increase in Tau-PS262 levels in primary neurons and brain tissues from the AD transgenic mice. Finally, caspase activation inhibitor Z-VAD and Aβ generation inhibitor L-685,458 attenuated the isoflurane-induced increases in Tau-PS262 levels. In conclusion, clinically relevant isoflurane anesthesia increases phosphorylated tau levels, which may result from the isoflurane-induced caspase activation and Aβ generation. These findings will promote more studies to determine the effects of anesthetics on tau phosphorylation. [ABSTRACT FROM AUTHOR]

The article focuses on a study which evaluates the effects of nitrous oxide and isoflurane on apoptosis and beta-amyloid levels in human neuroglioma cells and primary neurons from mice. In this study, cells or neurons and conditioned media that are exposed to nitrous oxide and isoflurane are harvested at the end of the treatment. Researchers determine the caspase-3 activation, apoptosis, processing of amyloid precursor protein (APP) and beta-amyloid levels. They conclude that apoptosis can enhance aspartyl protease beta-site APP-cleaving enzyme (BACE) levels to help APP processing.

Perioperative factors including hypoxia, hypocapnia, and certain anesthetics have been suggested to contribute to Alzheimer disease (AD) neuropathogenesis. Desflurane is one of the most commonly used inhalation anesthetics. However, the effects of desflurane on AD neuropathogenesis have not been previously determined. Here, we set out to assess the effects of desflurane and hypoxia on caspase activation, amyloid precursor protein (APP) processing, and amyloid β-protein (Aβ) generation in H4 human neuroglioma cells (H4 naïve cells) as well as those over-expressing APP (H4-APP cells). Neither 12% desflurane nor hypoxia (18% O2) alone affected caspase-3 activation, APP processing, and Aβ generation. However, treatment with a combination of 12% desflurane and hypoxia (18% O2) (desflurane/hypoxia) for 6 h induced caspase-3 activation, altered APP processing, and increased Aβ generation in H4-APP cells. Desflurane/hypoxia also increased levels of a-site APP-cleaving enzyme in H4-APP cells. In addition, desflurane/hypoxia-induced Aβ generation could be reduced by the broad caspase inhibitor benzyloxycarbonyl-VAD. Finally, the Aβ aggregation inhibitor clioquinol and γ-secretase inhibitor L-685,458 attenuated caspase-3 activation induced by desflurane/hypoxia. In summary, desflurane can induce Aβ production and caspase activation, but only in the presence of hypoxia. Pending in vivo confirmation, these data may have profound implications for anesthesia care in elderly patients, and especially those with AD. [ABSTRACT FROM AUTHOR]

Increasing evidence indicates that caspase activation and apoptosis are associated with a variety of neurodegenerative disorders, including Alzheimer's disease. We reported that anesthetic isoflurane can induce apoptosis, alter processing of the amyloid precursor protein (APP), and increase amyloid-β protein (Aβ) generation. However, the mechanism by which isoflurane induces apoptosis is primarily unknown. We therefore set out to assess effects of extracellular calcium concentration on isoflurane-induced caspase-3 activation in H4 human neuroglioma cells stably transfected to express human full-length APP (H4-APP cells). In addition, we tested effects of RNA interference (RNAi) silencing of IP3 receptor, NMDA receptor, and endoplasmic reticulum (ER) calcium pump, sacro-/ER calcium ATPase (SERCA1). Finally, we examined the effects of the NMDA receptor partial antagonist, memantine, inH4-APP cells and brain tissue of naive mice. EDTA (10 mM), BAPTA (10 µM), and RNAi silencing of IP3 receptor, NMDA receptor, or SERCA1 attenuated capase-3 activation. Memantine (4 µM) inhibited isoflurane-induced elevations in cytosolic calcium levels and attenuated isoflurane-induced caspase-3 activation, apoptosis, and cell viability. Memantine (20 mg/kg, i.p.) reduced isoflurane-induced caspase-3 activation in brain tissue of naive mice. These results suggest that disruption of calcium homeostasis underlies isoflurane-induced caspase activation and apoptosis. We also show for the first time that the NMDA receptor partial antagonist, memantine, can prevent isoflurane-induced caspase-3 activation and apoptosis in vivo and in vitro. These findings, indicating that isoflurane-induced caspase activation and apoptosis are dependent on cytosolic calcium levels, should facilitate the provision of safer anesthesia care, especially for Alzheimer's disease and elderly patients. [ABSTRACT FROM AUTHOR]

The anesthetic isoflurane has been reported to induce apoptosis and increase Aβ generation and aggregation. However, the molecular mechanism underlying these effects remains unknown. We therefore set out to assess whether the effects of isoflurane on apoptosis are linked to amyloid β-protein (Aβ) generation and aggregation. For this purpose, we assessed the effects of isoflurane on β-site amyloid β precursor protein (APP)-cleaving enzyme (BACE) and β-secretase, the proteases responsible for Aβ generation. We also tested the effects of inhibitors of Aβ aggregation (iAβ5, a β-sheet breaker peptide; clioquinol, a copper-zinc chelator) on the ability of isoflurane to induce apoptosis. All of these studies were performed on naive human H4 neuroglioma cells as well as those overexpressing APP (H4-APP cells). Isoflurane increased the levels of BACE and β-secretase and secreted Aβ in the H4-APP cells. Isoflurane-induced Aβ generation could be blocked by the broad-based caspase inhibitor Z-VAD. The Aβ aggregation inhibitors, iAβ5 and clioquinol, selectively attenuated caspase-3 activation induced by isoflurane. However, isoflurane was able to induce caspase-3 activation in the absence of any detectable alterations of Aβ generation in naive H4 cells. Finally, Aβ potentiated the isoflurane-induced caspase-3 activation in naive H4 cells. Collectively, these findings suggest that isoflurane can induce apoptosis, which, in turn, increases BACE and γ-secretase levels and Aβ secretion. Isoflurane also promotesAβ aggregation. Accumulation of aggregatedAβ in the media can then promote apoptosis. The result is a vicious cycle of isoflurane-induced apoptosis, Aβ generation and aggregation, and additional rounds of apoptosis, leading to cell death. [ABSTRACT FROM AUTHOR]

The inhalation anesthetic isoflurane has been reported to induce caspase activation and apoptosis, which may lead to learning and memory impairment. However, the underlying mechanisms of these effects are largely unknown. Isoflurane has been shown to induce elevation of cytosol calcium levels, accumulation of reactive oxygen species (ROS), opening of the mitochondrial permeability transition pore, reduction in mitochondria membrane potential, and release of cytochrome c. The time course of these effects, however, remains to be determined. Therefore, we performed a pilot study to determine the effects of treatment with isoflurane for various times on ROS levels in HEK-293 cells. The cells were treated with 2% isoflurane plus 21% O2 and 5% CO2 for 15, 30, 60, or 90 min. We then used fluorescence imaging and microplate fluorometer to detect ROS levels. We show that 2% isoflurane for 60 or 90 min, but not 15 or 30 min, induced ROS accumulation in the cells. These data illustrated that isoflurane could cause time-dependent effects on ROS levels. These findings have established a system to further determine the time course effects of isoflurane on cellular and mitochondria function. Ultimately, the studies would elucidate, at least partially, the underlying mechanisms of isoflurane-induced cellular toxicity. [ABSTRACT FROM AUTHOR]

The article focuses on a study which examined the effects of sevoflurane, an inhalation anesthetic, on caspase activation, apoptosis, β-amyloid protein levels and neuroinflammation in the brain tissues of neonatal naïve and Alzheimer disease (AD) transgenic mice. Brain cortex was harvested from the mouse decapitated after sevoflurane anesthesia was administered. The study demonstrated that sevoflurane anesthesia induced caspase activation and apoptosis and even altered amyloid precursor protein processing and increased &beta-;-amyloid protein levels in the brain tissues of neonatal mice. This indicates that neurotoxicity in neonatal mice may be induced by the said anesthetic.