Nitrous oxide plus isoflurane induces apoptosis and increases beta-amyloid protein levels.
BACKGROUND
Some anesthetics have been suggested to induce neurotoxicity, including promotion of Alzheimer's disease neuropathogenesis. Nitrous oxide and isoflurane are common anesthetics. The authors set out to assess the effects of nitrous oxide and/or isoflurane on apoptosis and beta-amyloid (Abeta) levels in H4 human neuroglioma cells and primary neurons from naïve mice.


METHODS
The cells or neurons were exposed to 70% nitrous oxide and/or 1% isoflurane for 6 h. The cells or neurons and conditioned media were harvested at the end of the treatment. Caspase-3 activation, apoptosis, processing of amyloid precursor protein, and Abeta levels were determined.


RESULTS
Treatment with a combination of 70% nitrous oxide and 1% isoflurane for 6 h induced caspase-3 activation and apoptosis in H4 naïve cells and primary neurons from naïve mice. The 70% nitrous oxide plus 1% isoflurane, but neither alone, for 6 h induced caspase-3 activation and apoptosis, and increased levels of beta-site amyloid precursor protein-cleaving enzyme and Abeta in H4-amyloid precursor protein cells. In addition, the nitrous oxide plus isoflurane-induced Abeta generation was reduced by a broad caspase inhibitor, Z-VAD. Finally, the nitrous oxide plus isoflurane-induced caspase-3 activation was attenuated by gamma-secretase inhibitor L-685,458, but potentiated by exogenously added Abeta.


CONCLUSIONS
These results suggest that the common anesthetics nitrous oxide plus isoflurane may promote neurotoxicity by inducing apoptosis and increasing Abeta levels. The generated Abeta may further potentiate apoptosis to form another round of apoptosis and Abeta generation. More studies, especially the in vivo confirmation of these in vitro findings, are needed.
Zhen
Yu
Y
Department of Anesthesia, Critical Care and Pain Medicine, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, 114 16th Street, Charlestown, MA 02129, USA.
Dong
Yuanlin
Y
Wu
Xu
X
Xu
Zhipeng
Z
Lu
Yan
Y
Zhang
Yiying
Y
Norton
David
D
Tian
Ming
M
Li
Shuren
S
Xie
Zhongcong
Z
D000199:Actins / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D018685:Anesthetics, Inhalation / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002219:Carbamates / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020287:In Situ Nick-End Labeling; D007530:Isoflurane / Q000633:toxicity*; D051379:Mice; D009474:Neurons / Q000187:drug effects; D009609:Nitrous Oxide / Q000633:toxicity*
D000199:Actins; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D018685:Anesthetics, Inhalation; D002219:Carbamates; D004151:Dipeptides; D004791:Enzyme Inhibitors; C410009:L 685458; D007530:Isoflurane; D053829:Amyloid Precursor Protein Secretases; D053148:Caspase 3; D009609:Nitrous Oxide