The Inhalation Anesthetic Isoflurane Induces a Vicious Cycle of Apoptosis and Amyloid β-Protein Accumulation

Abstract

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.

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

“…Given that these changes in calcium and the subsequent apoptosis could be largely suppressed by xestospongin C, our data strongly suggest that InsP 3 Rs may be the initial source of calcium and an upstream trigger for apoptosis. Furthermore, the up-regulation of BACE by isoflurane described in our results may contribute to the isoflurane-induced vicious cycle of apoptosis (Xie et al, 2007). Thus, our data suggest that the entire cascade of InsP 3 Rmediated calcium release and/or calcium influx and neurodegeneration can be prevented by the inhibition of InsP 3 Rs activity.…”

“…Given that isoflurane has been previously implicated in increasing the activity of BACE (Xie et al, 2007), Bcl-xl, and Bax (Wei et al, 2005), we investigated the effects of isoflurane treatment on the expression levels of these proteins and its relation with activation of InsP 3 Rs. As in previous studies (Xie et al, 2007;Zhen et al, 2009), isoflurane significantly increased levels of BACE, an enzyme that contributes to the production of ␤-amyloid and neuropathology in Alzheimer's disease. Interestingly, intracerebroventricular injection of xestospongin C before isoflurane exposure prevented this increase in BACE expression level (Fig.…”

“…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).…”

“…Moreover, it is not clear whether such excessive Ca 2ϩ release from the ER is a contributing factor in cognitive decline in rats exposed to isoflurane during early postnatal development. In this study, we examined whether isoflurane-induced neurodegeneration in rodent primary neuronal cell cultures and the developing brain occurs through disruption of intracellular calcium homeostasis via overactivation of the InsP 3 R. Isoflurane has been previously implicated in increasing the activity of the ␤-site amyloid ␤ precursor protein (APP)-cleaving enzyme (BACE) (Xie et al, 2007) and apoptosis regulatory proteins (Bcl-xl, Bax) (Wei et al, 2005). Thus, we investigated the relationship between the levels of these proteins and InsP 3 R activation.…”

Risk Factors for the Development of Post-Operative Cognitive Dysfunction

“…Furthermore, hypothermia during anaesthesia induces hyperphosphorylation of proteins by reducing the phosphatase 2a activity (Planel et al, 2008). Finally, it is noteworthy that anaesthesia, only at higher concentrations and prolonged periods, has been reported to produce pathological lesions similar to those of Alzheimer's disease but this is also a fact which is being disputed (Xie et al, 2006;Xie et al, 2007;Donk et al, 2012).…”