Objective-An estimated 200 million patients worldwide have surgery each year. Anesthesia and surgery have been reported to facilitate emergence of Alzheimer's disease (AD). The commonly used inhalation anesthetic isoflurane has previously been reported to induce apoptosis and to increase levels and aggregation of AD-associated amyloid β-protein (Aβ) in cultured cells. However, the in vivo relevance has not been addressed.Methods-We therefore set out to determine effects of isoflurane on caspase activation, levels of BACE and Aβ in naïve mice, employing Western blot, immunohistochemistry and RT-PCR.Results-Here we show for the first time that a clinically relevant isoflurane anesthesia (1.4% isoflurane for two hours) leads to caspase activation and modest increases in levels of the β-site APP-cleaving enzyme (BACE) six hours after anesthesia in mouse brain. Isoflurane anesthesia induces caspase activation, increases levels of BACE and Aβ up to 24 hours after anesthesia. Isoflurane may increase BACE levels by reducing BACE degradation. Moreover, the Aβ aggregation inhibitor, clioquinol, was able to attenuate isoflurane-induced caspase-3 activation in vivo.Interpretation-Given that transient insults to brain may lead to long term brain damage, these findings suggest that isoflurane may promote AD neuropathogenesis and, as such, have implications for use of isoflurane in humans, pending on human study confirmation.

A clinically relevant concentration of isoflurane induces apoptosis, alters APP processing, and increases Abeta production in a human neuroglioma cell line. Because altered processing of APP leading to accumulation of Abeta is a key event in the pathogenesis of Alzheimer disease, these findings may have implications for use of this anesthetic agent in individuals with excessive levels of cerebral Abeta and elderly patients at increased risk for postoperative cognitive dysfunction.

The anesthetic isoflurane has been reported to induce apoptosis and increase A␤ 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 ␤-protein (A␤) generation and aggregation. For this purpose, we assessed the effects of isoflurane on ␤-site amyloid ␤ precursor protein (APP)-cleaving enzyme (BACE) and ␥-secretase, the proteases responsible for A␤ generation. We also tested the effects of inhibitors of A␤ aggregation (iA␤5, a ␤-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 ␥-secretase and secreted A␤ in the H4-APP cells. Isoflurane-induced A␤ generation could be blocked by the broad-based caspase inhibitor Z-VAD. The A␤ aggregation inhibitors, iA␤5 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 A␤ generation in naive H4 cells. Finally, A␤ 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 ␥-secretase levels and A␤ secretion. Isoflurane also promotes A␤ aggregation. Accumulation of aggregated A␤ in the media can then promote apoptosis. The result is a vicious cycle of isoflurane-induced apoptosis, A␤ generation and aggregation, and additional rounds of apoptosis, leading to cell death.

Objective 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. Methods 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. Results 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. Interpretation 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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Isoflurane-nitrous oxide anesthesia is associated with a persistent deficit in RAM performance that is not explained by impaired locomotion. This impairment occurs in adult and aged rats, indicating that it is not an age-specific phenomenon. Thus, RAM performance is altered after general anesthesia for longer than predicted by the pharmacology of the drugs used, which, by inference, suggests a long-term deficit in learning/memory.

Anesthetics have been reported to promote Alzheimer's disease (AD) neuropathogenesis by inducing β-amyloid protein accumulation and apoptosis. Neuroinflammation is associated with the emergence of AD. We therefore set out to determine the effects of the common anesthetic isoflurane on the levels of TNF-α, IL-6, and IL-1β, the proinflammatory cytokines, in vitro and in vivo, employing Western blot, immunohistochemistry, ELISA, and RT-PCR. Here, we show that a clinically relevant isoflurane anesthesia increased the protein and mRNA levels of TNF-α, IL-6, and IL-1β in the brain tissues of mice. The isoflurane anesthesia increased the amounts of TNF-α immunostaining positive cells in the brain tissues of mice, the majority of which were neurons. Furthermore, isoflurane increased TNF-α levels in primary neurons, but not microglia cells, of mice. Finally, isoflurane induced a greater degree of TNF-α increase in the AD transgenic mice than in the wild type mice. These results suggest that isoflurane may increase the levels of proinflammatory cytokines, which may cause neuroinflammation, leading to promotion of AD neuropathogenesis.

This study demonstrates that general anesthesia with isoflurane and nitrous oxide improves spatial memory in young rats but impairs it in aged rats for at least 3 wk, indicating that it can influence memory for much longer than previously recognized and may adversely affect memory processes in the aged.