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.

Self-efficacy explains the influence of social support and depression on treatment adherence and may be a key target for interventions to improve disease management and self-care behaviors in HF patients.