Document Detail


The potential dual effects of anesthetic isoflurane on hypoxia-induced caspase-3 activation and increases in β-site amyloid precursor protein-cleaving enzyme levels.
MedLine Citation:
PMID:  21519046     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: β-Amyloid protein (Aβ) accumulation, caspase activation, apoptosis, and hypoxia-induced neurotoxicity have been suggested to be involved in Alzheimer disease neuropathogenesis. Aβ is produced from amyloid precursor protein through proteolytic processing by the aspartyl protease β-site amyloid precursor protein-cleaving enzyme (BACE) and γ-secretase. Inhaled anesthetics have long been considered to protect against neurotoxicity. However, recent studies have suggested that the inhaled anesthetic isoflurane may promote neurotoxicity by inducing caspase activation and apoptosis, and by increasing levels of BACE and Aβ. We therefore sought to determine whether isoflurane can induce concentration-dependent dual effects on hypoxia-induced caspase-3 activation and increases in BACE levels: protection versus promotion.
METHODS: H4 human neuroglioma cells were treated with hypoxia (3% O(2)) alone, different concentrations of isoflurane (0.5% and 2%), and the combination of hypoxia and 0.5% or 2% isoflurane. The levels of caspase-3 cleavage (activation), BACE, and Bcl-2 were determined by Western blot analysis.
RESULTS: We show for the first time that treatment with 0.5% isoflurane for 8 hours attenuated, whereas treatment with 2% isoflurane for 8 hours enhanced, hypoxia-induced caspase-3 activation and increases in BACE levels. The 2% isoflurane treatment also enhanced a hypoxia-induced decrease in Bcl-2 levels.
CONCLUSIONS: These results suggest a potential concept that isoflurane has dual effects (protection versus promotion) on hypoxia-induced toxicity, which may act through Bcl-2 family proteins. These findings could lead to more systematic studies to determine the potential dual effects of anesthetics on Alzheimer disease-associated neurotoxicity.
Authors:
Chuxiong Pan; Zhipeng Xu; Yuanlin Dong; Yiying Zhang; Jun Zhang; Sayre McAuliffe; Yun Yue; Tianzuo Li; Zhongcong Xie
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-04-25
Journal Detail:
Title:  Anesthesia and analgesia     Volume:  113     ISSN:  1526-7598     ISO Abbreviation:  Anesth. Analg.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-06-24     Completed Date:  2011-08-23     Revised Date:  2013-07-15    
Medline Journal Info:
Nlm Unique ID:  1310650     Medline TA:  Anesth Analg     Country:  United States    
Other Details:
Languages:  eng     Pagination:  145-52     Citation Subset:  AIM; IM    
Affiliation:
Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Room 4310, Charlestown, MA 02129-2060, USA.
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MeSH Terms
Descriptor/Qualifier:
Amyloid Precursor Protein Secretases / metabolism*
Amyloid beta-Peptides / metabolism
Amyloid beta-Protein Precursor / metabolism*
Anesthetics, Inhalation / adverse effects,  pharmacology*
Aspartic Acid Endopeptidases / metabolism*
Caspase 3 / metabolism*
Cell Hypoxia / drug effects,  physiology
Cell Line, Tumor
Dose-Response Relationship, Drug
Enzyme Activation / drug effects,  physiology
Humans
Isoflurane / adverse effects,  pharmacology*
Neuroprotective Agents / adverse effects,  pharmacology
Grant Support
ID/Acronym/Agency:
K08 NS048140/NS/NINDS NIH HHS; K08 NS048140-04/NS/NINDS NIH HHS; K08NS048140/NS/NINDS NIH HHS; R01 GM088801/GM/NIGMS NIH HHS; R01 GM088801/GM/NIGMS NIH HHS; R01 GM088801-02/GM/NIGMS NIH HHS; R01 GM088801-02S1/GM/NIGMS NIH HHS; R01 GM088801-04/GM/NIGMS NIH HHS; R21 AG029856/AG/NIA NIH HHS; R21 AG029856-02/AG/NIA NIH HHS; R21AG029856/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/Amyloid beta-Peptides; 0/Amyloid beta-Protein Precursor; 0/Anesthetics, Inhalation; 0/Neuroprotective Agents; 26675-46-7/Isoflurane; EC 3.4.-/Amyloid Precursor Protein Secretases; EC 3.4.22.-/Caspase 3; EC 3.4.23.-/Aspartic Acid Endopeptidases; EC 3.4.23.46/BACE1 protein, human
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