The potential dual effects of anesthetic isoflurane on Aβ-induced apoptosis.
β-amyloid protein (Aβ)-induced neurotoxicity is the main component of Alzheimer's disease (AD) neuropathogenesis. Inhalation anesthetics have long been considered to protect against neurotoxicity. However, recent research studies have suggested that the inhalation anesthetic isoflurane may promote neurotoxicity by inducing apoptosis and increasing Aβ levels. We therefore set out to determine whether isoflurane can induce dose- and time-dependent dual effects on Aβ-induced apoptosis: protection versus promotion. H4 human neuroglioma cells, primary neurons from naive mice, and naive mice were treated with Aβ and/or isoflurane, and levels of caspase-3 cleavage (activation), apoptosis, Bcl-2, Bax, and cytosolic calcium were determined. Here we show for the first time that the treatment with 2% isoflurane for six hours or 30 minutes potentiated, whereas the treatment with 0.5% isoflurane for six hours or 30 minutes attenuated, the Aβ-induced caspase-3 activation and apoptosis in vitro. Moreover, anesthesia with 1.4% isoflurane for two hours potentiated, whereas the anesthesia with 0.7% isoflurane for 30 minutes attenuated, the Aβ-induced caspase-3 activation in vivo. The high concentration isoflurane potentiated the Aβ-induced reduction in Bcl-2/Bax ratio and caused a robust elevation of cytosolic calcium levels. The low concentration isoflurane attenuated the Aβ-induced reduction in Bcl-2/Bax ratio and caused only a mild elevation of cytosolic calcium levels. These results suggest that isoflurane may have dual effects (protection or promotion) on Aβ-induced toxicity, which potentially act through the Bcl-2 family proteins and cytosolic calcium. These findings would lead to more systematic studies to determine the potential dual effects of anesthetics on AD-associated neurotoxicity.
Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129-2060, USA.
Zhipeng
Z
Xu
Yuanlin
Y
Dong
Xu
X
Wu
Jun
J
Zhang
Sayre
S
McAuliffe
Chuxiong
C
Pan
Yiying
Y
Zhang
Fumito
F
Ichinose
Yun
Y
Yue
Zhongcong
Z
Xie
D016229:Amyloid beta-Peptides / Q000633:toxicity; D018685:Anesthetics, Inhalation / Q000008:administration & dosage*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D020287:In Situ Nick-End Labeling; D007530:Isoflurane / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*
D016229:Amyloid beta-Peptides; D018685:Anesthetics, Inhalation; D007530:Isoflurane
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