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Isoflurane-Induced Apoptosis: A Potential Pathogenic Link Between Delirium and Dementia

¹ Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown.
² Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston.
³ Division of Gerontology, Beth Israel Deaconess Medical Center, Harvard Medical School, and the Aging Brain Center, Institute for Aging Research, Hebrew SeniorLife, Boston.
⁴ Department of Anesthesia, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Address correspondence to Rudolph E. Tanzi, PhD, Professor of Neurology (Neuroscience), Director, Genetics and Aging Research Unit, Massachusetts General Hospital/Harvard Medical School, 114 16th St. C3009, Charlestown, MA 02129-4404. E-mail: tanzi{at}helix.mgh.harvard.edu

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.

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