Perioperative Medicine  |   December 2017
Sevoflurane Acts on Ubiquitination–Proteasome Pathway to Reduce Postsynaptic Density 95 Protein Levels in Young Mice
Author Notes
  • From the Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (H.L., B.Y.); Department of Anesthesia, Critical Care and Medicine (H.L., N.L., Y.D., G.X., Y.Z., L.S., Z.X.) and Massachusetts General Hospital Biostatistics Center (H.Z.), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China (N.L.); First Affiliated Hospital, Anhui Medical University, Hefei, China (G.X.); School of Medicine and Health Sciences, George Washington University, Washington, D.C. (L.S.); and Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts (S.G.S.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication March 7, 2017. Accepted for publication August 23, 2017.
    Submitted for publication March 7, 2017. Accepted for publication August 23, 2017.×
  • Address correspondence to Dr. Xie: Massachusetts General Hospital and Harvard Medical School; 149 13th St., Room 4310, Charlestown, Massachusetts 02129-2060. zxie@mgh.harvard.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Basic Science / Central and Peripheral Nervous Systems / Pharmacology
Perioperative Medicine   |   December 2017
Sevoflurane Acts on Ubiquitination–Proteasome Pathway to Reduce Postsynaptic Density 95 Protein Levels in Young Mice
Anesthesiology 12 2017, Vol.127, 961-975. doi:10.1097/ALN.0000000000001889
Anesthesiology 12 2017, Vol.127, 961-975. doi:10.1097/ALN.0000000000001889
Abstract

Background: Children with multiple exposures to anesthesia and surgery may have an increased risk of developing cognitive impairment. Sevoflurane, a commonly used anesthetic in children, has been reported to decrease levels of postsynaptic density 95 protein. However, the upstream mechanisms and downstream consequences of the sevoflurane-induced reduction in postsynaptic density 95 protein levels remains largely unknown. We therefore set out to assess whether sevoflurane acts on ubiquitination–proteasome pathway to facilitate postsynaptic density 95 protein degradation.

Methods: Six-day-old wild-type mice received anesthesia with 3% sevoflurane 2 h daily for 3 days starting on postnatal day 6. We determined the effects of the sevoflurane anesthesia on mRNA, protein and ubiquitinated levels of postsynaptic density 95 protein in neurons, and synaptosomes and hippocampus of young mice. Cognitive function in the mice was determined at postnatal day 31 by using a Morris water maze. Proteasome inhibitor MG132 and E3 ligase mouse double mutant 2 homolog inhibitor Nutlin-3 were used for the interaction studies.

Results: The sevoflurane anesthesia decreased protein, but not mRNA, levels of postsynaptic density 95, and reduced ubiquitinated postsynaptic density 95 protein levels in neurons, synaptosomes, and hippocampus of young mice. Both MG132 and Nutlin-3 blocked these sevoflurane-induced effects. Sevoflurane promoted the interaction of mouse double mutant 2 homolog and postsynaptic density 95 protein in neurons. Finally, MG132 and Nutlin-3 ameliorated the sevoflurane-induced cognitive impairment in the mice.

Conclusions: These data suggest that sevoflurane acts on the ubiquitination–proteasome pathway to facilitate postsynaptic density 95 protein degradation, which then decreases postsynaptic density 95 protein levels, leading to cognitive impairment in young mice. These studies would further promote the mechanistic investigation of anesthesia neurotoxicity in the developing brain.