Newly Published
Perioperative Medicine  |   June 2017
Propofol Affects Neurodegeneration and Neurogenesis by Regulation of Autophagy via Effects on Intracellular Calcium Homeostasis
Author Notes
  • Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (H.Q., Y.L., Z.X., A.K., H.W.); Department of Anesthesiology, The Eye Ear Nose and Throat Hospital of Fudan University, Shanghai, People’s Republic of China (H.Q., W.L.); Department of Pain Medicine, Provincial Hospital Affiliated with Shandong University, Jinan, People’s Republic of China (Y.L., Z.F.); Department of Anesthesiology, First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China (Z.X.); and Department of Gerontology, Huashan Hospital of Fudan University, Shanghai, People’s Republic of China (Y.W.).
  • An abstract of this research work was presented at the Society for Neuroscience annual meeting in San Diego, California, November 14, 2016.
    An abstract of this research work was presented at the Society for Neuroscience annual meeting in San Diego, California, November 14, 2016.×
  • Submitted for publication July 19, 2016. Accepted for publication May 8, 2017.
    Submitted for publication July 19, 2016. Accepted for publication May 8, 2017.×
  • Acknowledgments: We appreciate the valuable discussions and support from Roderic G. Eckenhoff, M.D., Maryellen F. Eckenhoff, Ph.D., and Lee A. Fleisher, M.D., Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
    Acknowledgments: We appreciate the valuable discussions and support from Roderic G. Eckenhoff, M.D., Maryellen F. Eckenhoff, Ph.D., and Lee A. Fleisher, M.D., Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.×
  • Research Support: Supported by grant Nos. K08-GM073224, R01GM084979, 3R01GM084979-02S1, and 2R01GM084979-06A1 from the National Institute of General Medical Science, National Institutes of Health, Baltimore, Maryland (to Dr. Wei); research grant No. 12-FY08-167 from the March of Dimes Birth Defects Foundation, White Plains, New York (to Dr. Wei); and a bridging fund from the Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
    Research Support: Supported by grant Nos. K08-GM073224, R01GM084979, 3R01GM084979-02S1, and 2R01GM084979-06A1 from the National Institute of General Medical Science, National Institutes of Health, Baltimore, Maryland (to Dr. Wei); research grant No. 12-FY08-167 from the March of Dimes Birth Defects Foundation, White Plains, New York (to Dr. Wei); and a bridging fund from the Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Wei: Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, 3620 Hamilton Walk, 305 John Morgan Building, Philadelphia, Pennsylvania 19104. weih@uphs.upenn.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 / Pharmacology
Perioperative Medicine   |   June 2017
Propofol Affects Neurodegeneration and Neurogenesis by Regulation of Autophagy via Effects on Intracellular Calcium Homeostasis
Anesthesiology Newly Published on June 15, 2017. doi:10.1097/ALN.0000000000001730
Anesthesiology Newly Published on June 15, 2017. doi:10.1097/ALN.0000000000001730
Abstract

Background: In human cortical neural progenitor cells, we investigated the effects of propofol on calcium homeostasis in both the ryanodine and inositol 1,4,5-trisphosphate calcium release channels. We also studied propofol-mediated effects on autophagy, cell survival, and neuro- and gliogenesis.

Methods: The dose–response relationship between propofol concentration and duration was studied in neural progenitor cells. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and lactate dehydrogenase release assays. The effects of propofol on cytosolic calcium concentration were evaluated using Fura-2, and autophagy activity was determined by LC3II expression levels with Western blot. Proliferation and differentiation were evaluated by bromodeoxyuridine incorporation and immunostaining with neuronal and glial markers.

Results: Propofol dose- and time-dependently induced cell damage and elevated LC3II expression, most robustly at 200 µM for 24 h (67 ± 11% of control, n = 12 to 19) and 6 h (2.4 ± 0.5 compared with 0.6 ± 0.1 of control, n = 7), respectively. Treatment with 200 μM propofol also increased cytosolic calcium concentration (346 ± 71% of control, n = 22 to 34). Propofol at 10 µM stimulated neural progenitor cell proliferation and promoted neuronal cell fate, whereas propofol at 200 µM impaired neuronal proliferation and promoted glial cell fate (n = 12 to 20). Cotreatment with ryanodine and inositol 1,4,5-trisphosphate receptor antagonists and inhibitors, cytosolic Ca2+ chelators, or autophagy inhibitors mostly mitigated the propofol-mediated effects on survival, proliferation, and differentiation.

Conclusions: These results suggest that propofol-mediated cell survival or neurogenesis is closely associated with propofol’s effects on autophagy by activation of ryanodine and inositol 1,4,5-trisphosphate receptors.