Isoflurane-induced apoptosis: a potential pathogenic link between delirium and dementia.
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 beta-amyloid protein (Abeta) oligomerization and generation, to potentiate the cytotoxicity of Abeta, and to induce apoptosis. To address the molecular mechanisms of dementia and delirium associated with anesthesia and surgery, we assessed whether the Abeta fibrillar aggregation inhibitor Congo red can attenuate isoflurane-induced caspase-3 activation in H4 human neuroglioma cells overexpressing human beta-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.


CONCLUSIONS
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 Abeta oligomerization and apoptosis may contribute to the risk of postoperative cognitive dysfunction and provide a potential pathogenic link between delirium and dementia.
Xie
Zhongcong
Z
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129-4404, USA.
Dong
Yuanlin
Y
Maeda
Uta
U
Moir
Robert
R
Inouye
Sharon K
SK
Culley
Deborah J
DJ
Crosby
Gregory
G
Tanzi
Rudolph E
RE
D016564:Amyloid beta-Protein Precursor / Q000032:analysis; D018685:Anesthetics, Inhalation / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002478:Cells, Cultured; D003693:Delirium / Q000473:pathology*; D003704:Dementia / Q000473:pathology*; D006801:Humans; D007530:Isoflurane / Q000009:adverse effects / Q000494:pharmacology*; D009457:Neuroglia / Q000187:drug effects
D016564:Amyloid beta-Protein Precursor; D018685:Anesthetics, Inhalation; D007530:Isoflurane