[olsen]

The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 61:1300-1306 (2006)


Isoflurane-Induced Apoptosis: A Potential Pathogenic Link Between Delirium and Dementia
Zhongcong Xie, Yuanlin Dong, Uta Maeda, Robert Moir, Sharon K. Inouye, Deborah J. Culley, Gregory Crosby and Rudolph E. Tanzi


Background. Dementia and delirium have been postulated to share common pathophysiologic mechanisms; however, identification of these unifying mechanisms has remained elusive. The inhalation anesthetic isoflurane has been shown to enhance ß-amyloid protein (Aß) oligomerization and generation, to potentiate the cytotoxicity of Aß, and to induce apoptosis. To address the molecular mechanisms of dementia and delirium associated with anesthesia and surgery, we assessed whether the Aß fibrillar aggregation inhibitor Congo red can attenuate isoflurane-induced caspase-3 activation in H4 human neuroglioma cells overexpressing human ß-amyloid precursor protein (APP).

Methods. H4 human neuroglioma cells stably transfected to express human full-length wild-type APP were exposed to 2% isoflurane for 6 hours. The cells were harvested at the end of the treatment. Caspase-3 activation was measured with quantitative Western blotting.

Results. We found that isoflurane induces cellular apoptosis in a dose-dependent manner, and that Congo red inhibits isoflurane-induced apoptosis in H4 human neuroglioma cells overexpressing APP. Interestingly, Congo red also inhibits staurosporine-induced apoptosis.

Conclusion. The demonstration that isoflurane contributes to well-described mechanisms of Alzheimer's neuropathogenesis provides a plausible link between the acute effects of anesthesia, a well-described risk factor for delirium, and the more long-term sequelae of dementia. These findings suggest that isoflurane-induced Aß oligomerization and apoptosis may contribute to the risk of postoperative cognitive dysfunction and provide a potential pathogenic link between delirium and dementia.

ORIGINAL ARTICLE:

The Journal of Neuroscience, February 7, 2007, 27(6):1247-1254; doi:10.1523/JNEUROSCI.5320-06.2007
This Article

Neurobiology of Disease
The Inhalation Anesthetic Isoflurane Induces a Vicious Cycle of Apoptosis and Amyloid ß-Protein Accumulation

Zhongcong Xie,1,2 Yuanlin Dong,1,2 Uta Maeda,1,2 Robert D. Moir,1 Weiming Xia,3 Deborah J. Culley,4 Gregory Crosby,4 and Rudolph E. Tanzi1





The anesthetic isoflurane has been reported to induce apoptosis and increase Aß 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 ß-protein (Aß) generation and aggregation. For this purpose, we assessed the effects of isoflurane on ß-site amyloid ß precursor protein (APP)-cleaving enzyme (BACE) and -secretase, the proteases responsible for Aß generation. We also tested the effects of inhibitors of Aß aggregation (iAß5, a ß-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 Aß in the H4-APP cells. Isoflurane-induced Aß generation could be blocked by the broad-based caspase inhibitor Z-VAD. The Aß aggregation inhibitors, iAß5 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 Aß generation in naive H4 cells. Finally, Aß 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 Aß secretion. Isoflurane also promotes Aß aggregation. Accumulation of aggregated Aß in the media can then promote apoptosis. The result is a vicious cycle of isoflurane-induced apoptosis, Aß generation and aggregation, and additional rounds of apoptosis, leading to cell death.